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  • m6 A mRNA methylation sustains Treg suppressive functions
    Cell Res. (IF 15.606) Pub Date : 2018-01-05
    Jiyu Tong, Guangchao Cao, Ting Zhang,Esen Sefik, Maria Carolina Amezcua Vesely,James P Broughton, Shu Zhu, Huabin Li, Bin Li, Lei Chen, Howard Y Chang, Bing Su,Richard A Flavell, Hua-Bing Li

    N6-methyladenosine (m6 A) is the most abundant mRNA chemical modification, and is modulated by m6 A‘writers’, ‘erasers’ and ‘readers’ proteins [1-3]. In vitro experiments suggest that m6 A regulates several aspects of RNA metabolism, including RNA decay, splicing and translation [1]. Recent genetic analyses in vivo showed that m6 A functions in sex determination in Drosophila [4,5], in maternal-to-zygotic transition and haematopoietic stem cell specification during zebrafish embryogenesis [6, 7], in mouse spermatogenesis [8-10], and in mouse brain development [11]. We recently discovered that lineage-specific deletion of the m6 A ‘writer’ enzyme METTL3 in CD4+ T cells (Mettl3f/f; CD4-Cre) led to disruption of naïve T cell homeostasis [12]. CD4+ regulatory T cells (Tregs) comprise a critical subset of effector T cells, which are involved in resolution of inflammation and immunosuppression in tumor microenvironments [13]. However, the potential roles of m6 A mRNA modification in Treg functions in vivo are unknown.

    更新日期:2018-01-09
  • Cryo-EM structure of human ATR-ATRIP complex
    Cell Res. (IF 15.606) Pub Date : 2017-12-22
    Qinhui Rao, Mengjie Liu, Yuan Tian1,2,3, Zihan Wu, Yuhan Hao, Lei Song, Zhaoyu Qin, Chen Ding, Hong-Wei Wang, Jiawei Wang, Yanhui Xu

    ATR (ataxia telangiectasia-mutated and Rad3-related) protein kinase and ATRIP (ATR-interacting protein) form a complex and play a critical role in response to replication stress and DNA damage. Here, we determined the cryo-electron microscopy (EM) structure of the human ATR-ATRIP complex at 4.7 Å resolution and built an atomic model of the C-terminal catalytic core of ATR (residues 1 521-2 644) at 3.9 Å resolution. The complex adopts a hollow “heart” shape, consisting of two ATR monomers in distinct conformations. The EM map for ATRIP reveals 14 HEAT repeats in an extended “S” shape. The conformational flexibility of ATR allows ATRIP to properly lock the N-termini of the two ATR monomers to favor ATR-ATRIP complex formation and functional diversity. The isolated “head-head” and “tail-tail” each adopts a pseudo 2-fold symmetry. The catalytic pockets face outward and substrate access is not restricted by inhibitory elements. Our studies provide a structural basis for understanding the assembly of the ATRATRIP complex and a framework for characterizing ATR-mediated DNA repair pathways.

    更新日期:2017-12-31
  • Simple β-lactones are potent irreversible antagonists for strigolactone receptors
    Cell Res. (IF 15.606) Pub Date : 2017-12-31
    Haibo Xiang, Ruifeng Yao, Tianfei Quan, Fei Wang, Li Chen, Xiaoxi Du, Wenhao Zhang, Haiteng Deng, Daoxin Xie, Tuoping Luo

    Strigolactones (SLs) are a class of plant hormones that play vital roles not only in the control of plant branching and early seedling growth, but also in mediating rhizospheric communication with root parasitic plants and symbiotic fungi1. SL receptors in host and parasitic plants have recently been identified to be a group of α/β hydrolases2,3,4,5,6,7, but not in arbuscular mycorrhizal fungi, which form symbiosis with more than 80% of land plants8.

    更新日期:2017-12-31
  • Structural basis for BIR1-mediated negative regulation of plant immunity
    Cell Res. (IF 15.606) Pub Date : 2017-12-31
    Cuiyan Ma, Yanan Liu, Bing Bai, Zhifu Han, Jiao Tang, Heqiao Zhang, Hoda Yaghmaiean, Yuelin Zhang, Jijie Chai

    Plant receptor kinases (RKs) can function as pattern recognition receptors (PRRs) for perception of pathogen-associated molecular patterns (PAMPs) to induce immune responses1,2. One of such PRRs is the leucine-rich repeat RK (LRR-RK) FLAGELLIN-SENSING 2 (FLS2) that recognizes bacteria-derived flagellin (flg22 epitope)3,4. The smaller LRR-RK BRI1-associated kinase 1 (BAK1) acts as a co-receptor with FLS25,6.

    更新日期:2017-12-31
  • Structure of the fission yeast S. pombe telomeric Tpz1-Poz1-Rap1 complex
    Cell Res. (IF 15.606) Pub Date : 2017-12-31
    Jing Xue, Hongwen Chen, Jian Wu, Miho Takeuchi, Haruna Inoue, Yanmei Liu, Hong Sun, Yong Chen, Junko Kanoh, Ming Lei

    Telomeric shelterin complex caps chromosome ends and plays a crucial role in telomere maintenance and protection. In the fission yeast Schizosaccharomyces pombe, shelterin is composed of telomeric single- and double-stranded DNA-binding protein subcomplexes Pot1-Tpz1 and Taz1-Rap1, which are bridged by their interacting protein Poz1. However, the structure of Poz1 and how Poz1 functions as an interaction hub in the shelterin complex remain unclear. Here we report the crystal structure of Poz1 in complex with Poz1-binding motifs of Tpz1 and Rap1. The crystal structure shows that Poz1 employs two different binding surfaces to interact with Tpz1 and Rap1. Unexpectedly, the structure also reveals that Poz1 adopts a dimeric conformation. Mutational analyses suggest that proper interactions between Tpz1, Poz1, and Rap1 in the shelterin core complex are required for telomere length homeostasis and heterochromatin structure maintenance at telomeres. Structural resemblance between Poz1 and the TRFH domains of other shelterin proteins in fission yeast and humans suggests a model for the evolution of shelterin proteins.

    更新日期:2017-12-31
  • Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex
    Cell Res. (IF 15.606) Pub Date : 2017-12-31
    Chunyi Hu, Rekha Rai, Chenhui Huang, Cayla Broton, Juanjuan Long, Ying Xu, Jing Xue, Ming Lei, Sandy Chang, Yong Chen

    Telomeres are nucleoprotein complexes that play essential roles in protecting chromosome ends. Mammalian telomeres consist of repetitive DNA sequences bound by the shelterin complex. In this complex, the POT1-TPP1 heterodimer binds to single-stranded telomeric DNAs, while TRF1 and TRF2-RAP1 interact with double-stranded telomeric DNAs. TIN2, the linchpin of this complex, simultaneously interacts with TRF1, TRF2, and TPP1 to mediate the stable assembly of the shelterin complex. However, the molecular mechanism by which TIN2 interacts with these proteins to orchestrate telomere protection remains poorly understood. Here, we report the crystal structure of the N-terminal domain of TIN2 in complex with TIN2-binding motifs from TPP1 and TRF2, revealing how TIN2 interacts cooperatively with TPP1 and TRF2. Unexpectedly, TIN2 contains a telomeric repeat factor homology (TRFH)-like domain that functions as a protein-protein interaction platform. Structure-based mutagenesis analyses suggest that TIN2 plays an important role in maintaining the stable shelterin complex required for proper telomere end protection.

    更新日期:2017-12-31
  • Wnt-induced Vangl2 phosphorylation is dose-dependently required for planar cell polarity in mammalian development
    Cell Res. (IF 15.606) Pub Date : 2017-12-31
    Wei Yang, Lisa Garrett, Di Feng, Gene Elliott, Xilin Liu, Ni Wang, Yu Ming Wong, Nga Ting Choi, Yingzi Yang, Bo Gao

    Planar cell polarity (PCP) is an evolutionarily conserved essential mechanism that provides directional information to control and coordinate polarized cellular and tissue behavior during embryonic development. Disruption of PCP leads to severe morphological defects in vertebrates and its dysregulation results in a variety of human diseases such as neural tube defects and skeletal dysplasia. PCP is governed by a set of highly conserved core proteins that are asymmetrically localized at the cell surface throughout the polarized tissues. The uniform directionality of PCP is established by global cues, such as Wg/Wnt signaling gradients that break the original symmetrical localization of core PCP proteins including Vang/Vangl and Fz/Fzd. However, the exact mechanism remains elusive. In this study, we found that Vangl2 phosphorylation, which was previously identified to be induced by Wnt5a signaling, is required for Vangl2 functions in mammalian PCP in multiple tissues. The in vivo activities of Vangl2 are determined by its phosphorylation level. Phospho-mutant Vangl2 exhibits dominant negative effects, whereas Vangl2 with reduced phosphorylation is hypomorphic. We show that Vangl2 phosphorylation is essential for its uniform polarization pattern. Moreover, serine/threonine kinases CK1ε and CK1δ are redundantly required for Wnt5a-induced Vangl2 phosphorylation. Dvl family members are also required for Wnt5a-induced Vangl2 phosphorylation by enhancing the interaction of CK1 and Vangl2. These findings demonstrate that induction of Vangl protein phosphorylation plays an essential role in transducing Wnt5a signaling to establish PCP in mammalian development, suggesting a phosphorylation-regulated “Vangl activity gradient” model in addition to the well-documented “Fz activity gradient” model in Wnt/PCP signaling.

    更新日期:2017-12-31
  • Suppression of MAPK11 or HIPK3 reduces mutant Huntingtin levels in Huntington's disease models
    Cell Res. (IF 15.606) Pub Date : 2017-12-31
    Meng Yu, Yuhua Fu, Yijiang Liang, Haikun Song, Yao Yao, Peng Wu, Yuwei Yao, Yuyin Pan, Xue Wen, Lixiang Ma, Saiyin Hexige, Yu Ding, Shouqing Luo, Boxun Lu

    Most neurodegenerative disorders are associated with accumulation of disease-relevant proteins. Among them, Huntington disease (HD) is of particular interest because of its monogenetic nature. HD is mainly caused by cytotoxicity of the defective protein encoded by the mutant Huntingtin gene (HTT). Thus, lowering mutant HTT protein (mHTT) levels would be a promising treatment strategy for HD. Here we report two kinases HIPK3 and MAPK11 as positive modulators of mHTT levels both in cells and in vivo. Both kinases regulate mHTT via their kinase activities, suggesting that inhibiting these kinases may have therapeutic values. Interestingly, their effects on HTT levels are mHTT-dependent, providing a feedback mechanism in which mHTT enhances its own level thus contributing to mHTT accumulation and disease progression. Importantly, knockout of MAPK11 significantly rescues disease-relevant behavioral phenotypes in a knockin HD mouse model. Collectively, our data reveal new therapeutic entry points for HD and target-discovery approaches for similar diseases.

    更新日期:2017-12-31
  • Twa1/Gid8 is a β-catenin nuclear retention factor in Wnt signaling and colorectal tumorigenesis
    Cell Res. (IF 15.606) Pub Date : 2017-12-31
    Yi Lu, Shanshan Xie, Wen Zhang, Cheng Zhang, Cheng Gao, Qiang Sun, Yuqi Cai, Zhangqi Xu, Min Xiao, Yanjun Xu, Xiao Huang, Ximei Wu, Wei Liu, Fudi Wang, Yibin Kang, Tianhua Zhou

    Hyperactivation of Wnt/β-catenin signaling is one of the major causes of human colorectal cancer (CRC). A hallmark of Wnt signaling is the nuclear accumulation of β-catenin. Although β-catenin nuclear import and export have been widely investigated, the underlying mechanism of β-catenin's nuclear retention remains largely unknown. Here, we report that Twa1/Gid8 is a key nuclear retention factor for β-catenin during Wnt signaling and colorectal carcinogenesis. In the absence of Wnt, Twa1 exists together with β-catenin in the Axin complex and undergoes ubiquitination and degradation. Upon Wnt signaling, Twa1 translocates into the nucleus, where it binds and retains β-catenin. Depletion of Twa1 attenuates Wnt-stimulated gene expression, dorsal development of zebrafish embryos and xenograft tumor growth of CRC cells. Moreover, nuclear Twa1 is significantly upregulated in human CRC tissues, correlating with the nuclear accumulation of β-catenin and poor prognosis. Thus, our results identify Twa1 as a previously undescribed regulator of the Wnt pathway for promoting colorectal tumorigenesis by facilitating β-catenin nuclear retention.

    更新日期:2017-12-31
  • H7N9 virulent mutants detected in chickens in China pose an increased threat to humans
    Cell Res. (IF 15.606) Pub Date : 2017-12-31
    Jianzhong Shi, Guohua Deng, Huihui Kong, Chunyang Gu, Shujie Ma, Xin Yin, Xianying Zeng, Pengfei Cui, Yan Chen, Huanliang Yang, Xiaopeng Wan, Xiurong Wang, Liling Liu, Pucheng Chen, Yongping Jiang, Jinxiong Liu, Yuntao Guan, Yasuo Suzuki, Mei Li, Zhiyuan Qu, Lizheng Guan, Jinkai Zang, Wenli Gu, Shuyu Han, Yangming Song, Yuzhen Hu, Zeng Wang, Linlin Gu, Wenyu Yang, Libin Liang, Hongmei Bao, Guobin Tian, Yanbing Li, Chuanling Qiao, Li Jiang, Chengjun Li, Zhigao Bu, Hualan Chen

    Certain low pathogenic avian influenza viruses can mutate to highly pathogenic viruses when they circulate in domestic poultry, at which point they can cause devastating poultry diseases and severe economic damage. The H7N9 influenza viruses that emerged in 2013 in China had caused severe human infections and deaths. However, these viruses were nonlethal in poultry. It is unknown whether the H7N9 viruses can acquire additional mutations during their circulation in nature and become lethal to poultry and more dangerous for humans. Here, we evaluated the evolution of H7N9 viruses isolated from avian species between 2013 and 2017 in China and found 23 different genotypes, 7 of which were detected only in ducks and were genetically distinct from the other 16 genotypes that evolved from the 2013 H7N9 viruses. Importantly, some H7N9 viruses obtained an insertion of four amino acids in their hemagglutinin (HA) cleavage site and were lethal in chickens. The index strain was not lethal in mice or ferrets, but readily obtained the 627K or 701N mutation in its PB2 segment upon replication in ferrets, causing it to become highly lethal in mice and ferrets and to be transmitted efficiently in ferrets by respiratory droplet. H7N9 viruses bearing the HA insertion and PB2 627K mutation have been detected in humans in China. Our study indicates that the new H7N9 mutants are lethal to chickens and pose an increased threat to human health, and thus highlights the need to control and eradicate the H7N9 viruses to prevent a possible pandemic.

    更新日期:2017-12-31
  • Fine-tuning type I IFN signaling: A new chapter in the IFN saga
    Cell Res. (IF 15.606) Pub Date : 2017-12-31
    Hideyuki Yanai, Tadatsugu Taniguchi

    Type I interferon (IFN) signaling is critical for intracellular antimicrobial programmes, affecting both innate and adaptive immune responses. The paper recently published in Cell demonstrates a new regulatory mechanism of the type I IFN signaling pathway by histone-lysine N-methyltransferase SETD2.

    更新日期:2017-12-31
  • TDP2, TOP2, and SUMO: what is ZATT about?
    Cell Res. (IF 15.606) Pub Date : 2017-12-31
    Guido Zagnoli-Vieira, Keith W Caldecott

    Recently, ZATT (also known as ZNF451 or Zpf451) was reported by Schellenberg et al. to aid the removal of Topoisomerase II cleavage complexes by stimulating the phosphodiesterase activity of Tyrosyl DNA Phosphodiesterase 2. Although the full implication of this discovery is unknown, it will help us understand how cells respond to topoisomerase-induced genome damage and chemotherapeutic topoisomerase 'poisons'.

    更新日期:2017-12-31
  • Hunting for the mutant without the MAP(K)
    Cell Res. (IF 15.606) Pub Date : 2017-12-31
    Leon Tejwani, Janghoo Lim

    In a paper recently published in Cell Research, Yu et al. identify two MAPK-related kinases, MAPK11 and HIPK3, as positive regulators of levels of mutant huntingtin protein, a toxic species highly involved in Huntington’s disease (HD) pathology. The identification and validation of these kinases as therapeutic targets for knockdown in multiple relevant experimental model systems reveal novel potential approaches for treatment of HD.

    更新日期:2017-12-31
  • A circular twist on microRNA regulation
    Cell Res. (IF 15.606) Pub Date : 2017-12-31
    Marco Bezzi, Jlenia Guarnerio, Pier Paolo Pandolfi

    Circular RNAs (circRNAs) are a novel class of RNA whose physiological function has yet to be investigated. A recent publication in Science provides the first evidence of the biological relevance of a circRNA in an in vivo model and unveils an unexpected twist on their crosstalk with miRNAs.

    更新日期:2017-12-31
  • Chemically synthesized histone H2A Lys13 di-ubiquitination promotes binding of 53BP1 to nucleosomes
    Cell Res. (IF 15.606) Pub Date : 2017-12-15
    Jia-Bin Li, Yun-Kun Qi, Qiao-Qiao He,Hua-Song Ai, San-ling Liu, Jia-Xing Wang,Ji-Shen Zheng, Lei Liu, Changlin Tian

    p53-binding protein 1 (53BP1) is a critical regulator of cellular response to DNA double-strand breaks (DSBs) [1]. To accomplish its repair function, 53BP1 must be recruited to the chromatin surrounding DSB sites that carry H4 methylation at Lys20 and H2A ubiquitination at Lys15 [2-5]. The structural basis of this recognition process was recently revealed by the complex structure of 53BP1 bound to a nucleosome core particle (NCP) containing Lys20-dimethylated H4 (H4K20me2) and Lys15-mono-ubiquitinated H2A (H2AK15monoUb) [6]. It is fascinating to note that ubiquitin ligase RNF168 ubiquitinated H2A not only on Lys15, but also on Lys13 without selectivity, and H2A bearing the K15Q mutation was still poly-ubiquitinated at Lys13 in vivo [2-4, 7]. This leads to two questions. First, is 53BP1 also a reader of H2A Lys13 ubiquitin mark? Second, is poly-ubiquitination redundant at the 53BP1 recruitment event?

    更新日期:2017-12-21
  • New traffic light on Th17 Avenue
    Cell Res. (IF 15.606) Pub Date : 2017-12-08
    Hao Xu, Dan R Littman

    Activation of STAT3-coupled receptors along with TGF-β signaling are fundamental for Th17 cell differentiation both in vivo and in vitro. A recent paper shows that TGF-β signaling relieves SKI-mediated transcriptional repression of Rorc, the key regulator of the Th17 program.

    更新日期:2017-12-15
  • Mitochondrial metabolism and cancer
    Cell Res. (IF 15.606) Pub Date : 2017-12-08
    Paolo Ettore Porporato, Nicoletta Filigheddu, Jose Manuel Bravo-San Pedro, Guido Kroemer, Lorenzo Galluzzi

    Glycolysis has long been considered as the major metabolic process for energy production and anabolic growth in cancer cells. Although such a view has been instrumental for the development of powerful imaging tools that are still used in the clinics, it is now clear that mitochondria play a key role in oncogenesis. Besides exerting central bioenergetic functions, mitochondria provide indeed building blocks for tumor anabolism, control redox and calcium homeostasis, participate in transcriptional regulation, and govern cell death. Thus, mitochondria constitute promising targets for the development of novel anticancer agents. However, tumors arise, progress, and respond to therapy in the context of an intimate crosstalk with the host immune system, and many immunological functions rely on intact mitochondrial metabolism. Here, we review the cancer cell-intrinsic and cell-extrinsic mechanisms through which mitochondria influence all steps of oncogenesis, with a focus on the therapeutic potential of targeting mitochondrial metabolism for cancer therapy.

    更新日期:2017-12-15
  • Structural basis for specific flagellin recognition by the NLR protein NAIP5
    Cell Res. (IF 15.606) Pub Date : 2017-11-28
    Xinru Yang, Fan Yang, Weiguang Wang, Guangzhong Lin, Zehan Hu, Zhifu Han, Yijun Qi,
    Liman Zhang, Jiawei Wang, Sen-Fang Sui, Jijie Chai

    The nucleotide-binding domain- and leucine-rich repeat (LRR)-containing proteins (NLRs) function as intracellular immune receptors to detect the presence of pathogen- or host-derived signals. The mechanisms of how NLRs sense their ligands remain elusive. Here we report the structure of a bacterial flagellin derivative in complex with the NLR proteins NAIP5 and NLRC4 determined by cryo-electron microscopy at 4.28 Å resolution. The structure revealed that the flagellin derivative forms two parallel helices interacting with multiple domains including BIR1 and LRR of NAIP5. Binding to NAIP5 results in a nearly complete burial of the flagellin derivative, thus stabilizing the active conformation of NAIP5. The extreme C-terminal side of the flagellin is anchored to a sterically constrained binding pocket of NAIP5, which likely acts as a structural determinant for discrimination of different bacterial flagellins by NAIP5, a notion further supported by biochemical data. Taken together, our results shed light on the molecular mechanisms underlying NLR ligand perception.

    更新日期:2017-12-01
  • Pairing of integrins with ECM proteins determines migrasome formation
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Danni Wu, Yue Xu, Tianlun Ding, Yan Zu, Chun Yang, Li Yu1

    Recently we reported the discovery of migrasome, a new organelle of migrating cells1. Migrasomes are large vesicles that grow on the tips or intersections of retraction fibers at the rear of migrating cells. Following cell migration, the retraction fibers eventually break and the migrasomes become detached. The migrasomes and their contents, including cytosolic components and vesicles of unknown origin, are released into the extracellular space —— a process we named as migracytosis. We speculated that migracytosis may play important roles in cell-cell communication.

    更新日期:2017-11-06
  • An essential role for PNLDC1 in piRNA 3′ end trimming and male fertility in mice
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Yue Zhang, Rui Guo, Yiqiang Cui, Zhiping Zhu, Yingwen Zhang, Hao Wu, Bo Zheng, Qiuling Yue, Shun Bai, Wentao Zeng, Xuejiang Guo, Zuomin Zhou, Bin Shen, Ke Zheng, Mingxi Liu, Lan Ye, Jiahao Sha

    PIWI-interacting RNAs (piRNAs) are germ cell-specific small non-coding RNAs that are essential for silencing transposable elements. Substantial efforts in the past decade have led to an understanding of how piRNAs are made. Primary piRNA biogenesis is initiated with transcription of piRNA precursors, followed by cleavage into piRNA intermediates, and finally, maturation by 3′ end trimming and 2′-O-methylation. Secondary piRNA biogenesis occurs through an amplification loop (ping pong pathway); the piRNA pools generated through primary processing guide MILI protein to cleave the target RNA for piRNA generation in a feed-forward loop that accelerates production of the piRNAs. Papi/Tdrkh has been implicated in processing the 3′ ends of piRNAs1,2, however, Papi/Tdrkh lacks a recognized domain for nuclease activity. Recently, two independent studies identified the proteins that function as piRNA 3′ end trimmers in silkworms-the poly(A) specific ribonuclease PARN-1 and the PARN-like ortholog PNLDC13,4.

    更新日期:2017-11-06
  • Structural and mechanistic insights into the biosynthesis of CDP-archaeol in membranes
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Sixue Ren, Antonella Caforio, Qin Yang, Bo Sun, Feng Yu, Xiaofeng Zhu, Jinjing Wang, Chao Dou, Qiuyu Fu, Niu Huang, Qiu Sun, Chunlai Nie, Shiqian Qi, Xinqi Gong, Jianhua He, Yuquan Wei, Arnold JM Driessen, Wei Cheng

    The divergence of archaea, bacteria and eukaryotes was a fundamental step in evolution. One marker of this event is a major difference in membrane lipid chemistry between these kingdoms. Whereas the membranes of bacteria and eukaryotes primarily consist of straight fatty acids ester-bonded to glycerol-3-phosphate, archaeal phospholipids consist of isoprenoid chains ether-bonded to glycerol-1-phosphate. Notably, the mechanisms underlying the biosynthesis of these lipids remain elusive. Here, we report the structure of the CDP-archaeol synthase (CarS) of Aeropyrum pernix (ApCarS) in the CTP- and Mg2+-bound state at a resolution of 2.4 Å. The enzyme comprises a transmembrane domain with five helices and cytoplasmic loops that together form a large charged cavity providing a binding site for CTP. Identification of the binding location of CTP and Mg2+ enabled modeling of the specific lipophilic substrate-binding site, which was supported by site-directed mutagenesis, substrate-binding affinity analyses, and enzyme assays. We propose that archaeol binds within two hydrophobic membrane-embedded grooves formed by the flexible transmembrane helix 5 (TM5), together with TM1 and TM4. Collectively, structural comparisons and analyses, combined with functional studies, not only elucidated the mechanism governing the biosynthesis of phospholipids with ether-bonded isoprenoid chains by CTP transferase, but also provided insights into the evolution of this enzyme superfamily from archaea to bacteria and eukaryotes.

    更新日期:2017-11-06
  • Molecular mechanism of directional CTCF recognition of a diverse range of genomic sites
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Maolu Yin, Jiuyu Wang, Min Wang, Xinmei Li, Mo Zhang, Qiang Wu, Yanli Wang

    CTCF, a conserved 3D genome architecture protein, determines proper genome-wide chromatin looping interactions through directional binding to specific sequence elements of four modules within numerous CTCF-binding sites (CBSs) by its 11 zinc fingers (ZFs). Here, we report four crystal structures of human CTCF in complex with CBSs of the protocadherin (Pcdh) clusters. We show that directional CTCF binding to cognate CBSs of the Pcdh enhancers and promoters is achieved through inserting its ZF3, ZFs 4-7, and ZFs 9-11 into the major groove along CBSs, resulting in a sequence-specific recognition of module 4, modules 3 and 2, and module 1, respectively; and ZF8 serves as a spacer element for variable distances between modules 1 and 2. In addition, the base contact with the asymmetric “A” in the central position of modules 2-3, is essential for directional recognition of the CBSs with symmetric core sequences but lacking module 1. Furthermore, CTCF tolerates base changes at specific positions within the degenerated CBS sequences, permitting genome-wide CTCF binding to a diverse range of CBSs. Together, these complex structures provide important insights into the molecular mechanisms for the directionality, diversity, flexibility, dynamics, and conservation of multivalent CTCF binding to its cognate sites across the entire human genome.

    更新日期:2017-11-06
  • A vital sugar code for ricin toxicity
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Jasmin Taubenschmid, Johannes Stadlmann, Markus Jost, Tove Irene Klokk, Cory D Rillahan, Andreas Leibbrandt, Karl Mechtler, James C Paulson, Julian Jude, Johannes Zuber, Kirsten Sandvig, Ulrich Elling, Thorsten Marquardt, Christian Thiel, Christian Koerner, Josef M Penninger

    Ricin is one of the most feared bioweapons in the world due to its extreme toxicity and easy access. Since no antidote exists, it is of paramount importance to identify the pathways underlying ricin toxicity. Here, we demonstrate that the Golgi GDP-fucose transporter Slc35c1 and fucosyltransferase Fut9 are key regulators of ricin toxicity. Genetic and pharmacological inhibition of fucosylation renders diverse cell types resistant to ricin via deregulated intracellular trafficking. Importantly, cells from a patient with SLC35C1 deficiency are also resistant to ricin. Mechanistically, we confirm that reduced fucosylation leads to increased sialylation of Lewis X structures and thus masking of ricin-binding sites. Inactivation of the sialyltransferase responsible for modifications of Lewis X (St3Gal4) increases the sensitivity of cells to ricin, whereas its overexpression renders cells more resistant to the toxin. Thus, we have provided unprecedented insights into an evolutionary conserved modular sugar code that can be manipulated to control ricin toxicity.

    更新日期:2017-11-06
  • Cryo-EM structure of human DNA-PK holoenzyme
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Xiaotong Yin, Mengjie Liu, Yuan Tian, Jiawei Wang, Yanhui Xu

    DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase complex composed of a catalytic subunit (DNA-PKcs) and KU70/80 heterodimer bound to DNA. DNA-PK holoenzyme plays a critical role in non-homologous end joining (NHEJ), the major DNA repair pathway. Here, we determined cryo-electron microscopy structure of human DNA-PK holoenzyme at 6.6 Å resolution. In the complex structure, DNA-PKcs, KU70, KU80 and DNA duplex form a 650-kDa heterotetramer with 1:1:1:1 stoichiometry. The N-terminal α-solenoid (~2 800 residues) of DNA-PKcs adopts a double-ring fold and connects the catalytic core domain of DNA-PKcs and KU70/80-DNA. DNA-PKcs and KU70/80 together form a DNA-binding tunnel, which cradles ~30-bp DNA and prevents sliding inward of DNA-PKcs along with DNA duplex, suggesting a mechanism by which the broken DNA end is protected from unnecessary processing. Structural and biochemical analyses indicate that KU70/80 and DNA coordinately induce conformational changes of DNA-PKcs and allosterically stimulate its kinase activity. We propose a model for activation of DNA-PKcs in which allosteric signals are generated upon DNA-PK holoenzyme formation and transmitted to the kinase domain through N-terminal HEAT repeats and FAT domain of DNA-PKcs. Our studies suggest a mechanism for recognition and protection of broken DNA ends and provide a structural basis for understanding the activation of DNA-PKcs and DNA-PK-mediated NHEJ pathway.

    更新日期:2017-11-06
  • A high-quality genome assembly of quinoa provides insights into the molecular basis of salt bladder-based salinity tolerance and the exceptional nutritional value
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Changsong Zou, Aojun Chen, Lihong Xiao, Heike M Muller, Peter Ache, Georg Haberer, Meiling Zhang, Wei Jia, Ping Deng, Ru Huang, Daniel Lang, Feng Li, Dongliang Zhan, Xiangyun Wu, Hui Zhang, Jennifer Bohm, Renyi Liu, Sergey Shabala, Rainer Hedrich, Jian-Kang Zhu, Heng Zhang

    Chenopodium quinoa is a halophytic pseudocereal crop that is being cultivated in an ever-growing number of countries. Because quinoa is highly resistant to multiple abiotic stresses and its seed has a better nutritional value than any other major cereals, it is regarded as a future crop to ensure global food security. We generated a high-quality genome draft using an inbred line of the quinoa cultivar Real. The quinoa genome experienced one recent genome duplication about 4.3 million years ago, likely reflecting the genome fusion of two Chenopodium parents, in addition to the γ paleohexaploidization reported for most eudicots. The genome is highly repetitive (64.5% repeat content) and contains 54 438 protein-coding genes and 192 microRNA genes, with more than 99.3% having orthologous genes from glycophylic species. Stress tolerance in quinoa is associated with the expansion of genes involved in ion and nutrient transport, ABA homeostasis and signaling, and enhanced basal-level ABA responses. Epidermal salt bladder cells exhibit similar characteristics as trichomes, with a significantly higher expression of genes related to energy import and ABA biosynthesis compared with the leaf lamina. The quinoa genome sequence provides insights into its exceptional nutritional value and the evolution of halophytes, enabling the identification of genes involved in salinity tolerance, and providing the basis for molecular breeding in quinoa.

    更新日期:2017-11-06
  • Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Kyoung-Han Kim, Yun Hye Kim, Joe Eun Son, Ju Hee Lee, Sarah Kim, Min Seon Choe, Joon Ho Moon, Jian Zhong, Kiya Fu, Florine Lenglin, Jeong-Ah Yoo, Philip J Bilan, Amira Klip, Andras Nagy, Jae-Ryong Kim, Jin Gyoon Park, Samer MI Hussein, Kyung-Oh Doh, Chi-chung Hui, Hoon-Ki Sung

    Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor (VEGF) expression in white adipose tissue (WAT). Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders.

    更新日期:2017-11-06
  • tsRNAs: new players in mammalian retrotransposon control
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Yunfang Zhang, Junchao Shi, Qi Chen

    A recent study led by Professor Rob Martienssen in Cell showed that 3′-tRNA-derived small RNAs can suppress long terminal repeat retrotransposon activity in mammalian cells by mechanisms independent of DNA-associated epigenetic marks, suggesting how the genome may defend itself from retrotransposon invasion during epigenetic reprogramming.

    更新日期:2017-11-06
  • Structural step forward for NHEJ
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Go Watanabe, Michael R Lieber, Dewight Williams

    In a recent paper published in Cell Research, a cryo-EM structure reveals the interface between DNA-PKcs and the Ku70/80:DNA complex, together forming the DNA-dependent protein kinase holoenzyme in non-homologous DNA end joining. Insight from this structure suggests how an allosteric rearrangement of DNA-PKcs driven by Ku70/80:DNA binding regulates kinase activity in this largest member of a family of structurally homologous phosphoinositide 3-kinase-related protein kinases that includes mTOR, ATR, and ATM.

    更新日期:2017-11-06
  • NLRP9b: a novel RNA-sensing inflammasome complex
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Chinh Ngo, Si Ming Man

    Inflammasome sensors recognize pathogens and danger signals and assemble an immune signaling complex, which induces the secretion of pro-inflammatory cytokines IL-1β and IL-18, and pyroptosis. A new study published in Nature now describes a new inflammasome sensor NLRP9b in intestinal epithelial cells, which in concert with the RNA sensor DHX9, recognize short dsRNA from Rotavirus.

    更新日期:2017-11-06
  • White adipose tissue coloring by intermittent fasting
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Riikka Kivelä, Kari Alitalo

    Intermittent fasting (IF) has been shown to promote metabolic health in several organisms. Two recent papers show that IF induces white adipose tissue beiging and increases thermogenesis, which improves metabolic health in mice.

    更新日期:2017-11-06
  • Sanofi-Cell Research outstanding paper award of 2016
    Cell Res. (IF 15.606) Pub Date : 2017-11-06
    Editorial Office

    None

    更新日期:2017-11-06
  • Human embryonic stem cells contribute to embryonic and extraembryonic lineages in mouse embryos upon inhibition of apoptosis
    Cell Res. (IF 15.606) Pub Date : 2017-11-03
    Xuepeng Wang, Tianda Li, Tongtong Cui, Dawei Yu, Chao Liu, Liyuan Jiang, Guihai Feng, Lei Wang, Rui Fu, Xinxin Zhang, Jie Hao, Yukai Wang, Liu Wang, Qi Zhou, Wei Li, Baoyang Hu

    Recently, interspecies chimera formation has been established in rodents by injection of rat pluripotent stem cells (PSCs) into mouse early embryos, and such a system provides an in vivo assay to test the developmental potential of human PSCs (hPSCs)1. In addition, the interspecies chimeras formed between hPSCs and large animal embryos would open new avenues to generate human tissues and organs for regenerative medicine2. In rodents, embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) have been derived from inner cell mass (ICM) of the blastocyst and post-implantation epiblast respectively3,4. Although both being pluripotent, the ESCs and EpiSCs are considered to represent two distinct states of pluripotency, the naïve and primed pluripotent state. Only naïve state ESCs can colonize the early embryos before the blastocyst stage to form adult chimeras and transmit to the germline, while the primed state EpiSCs can only integrate into the post-implantation embryos5,6. Intriguingly, although derived from the ICM, the human ESCs (hESCs) are similar to the mouse EpiSCs in many aspects such as the morphology and self-renewal pathways, hence they are considered to represent the primed pluripotent state. Several studies have reported the generation of human-animal interspecies chimeras using the stage-matching hESCs. For example, primed hPSCs were engrafted into in vitro cultured gastrula-stage mouse embryos to form chimeras, and the primed hPSCs were also converted into a naïve-like state and then were injected into pre-implantation embryos to form mouse or pig chimeras7,8,9.

    更新日期:2017-11-06
  • Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage
    Cell Res. (IF 15.606) Pub Date : 2017-10-17
    Kyoung-Han Kim, Yun Hye Kim, Joe Eun Son, Ju Hee Lee, Sarah Kim, Min Seon Choe, Joon Ho Moon, Jian Zhong, Kiya Fu, Florine Lenglin, Jeong-Ah Yoo, Philip J Bilan, Amira Klip, Andras Nagy, Jae-Ryong Kim, Jin Gyoon Park, Samer MI Hussein, Kyung-Oh Doh, Chi-chung Hui, Hoon-Ki Sung

    Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor (VEGF) expression in white adipose tissue (WAT). Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders.

    更新日期:2017-10-18
  • Altered neurogenesis and disrupted expression of synaptic proteins in prefrontal cortex of SHANK3-deficient non-human primate
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Hui Zhao, Zhuchi Tu, Huijuan Xu, Sen Yan, Huanhuan Yan, Yinghui Zheng, Weili Yang, Jiezhao Zheng, Zhujun Li, Rui Tian, Youming Lu, Xiangyu Guo, Yong-hui Jiang, Xiao-Jiang Li, Yong Q Zhang

    Despite substantial progress made toward understanding the molecular changes contributing to autism spectrum disorders (ASD), the neuropathophysiology underlying ASD remains poorly understood1,2. Structural brain imaging in humans is valuable, but lacks resolution at the cellular level. Studies of neuropathology in humans have been hampered by the lack of high quality postmortem brains from individuals with ASD2. For more than decades, mutant mice have served as major tools to dissect the pathophysiology of ASD because of the wealth of molecular and neurobiological techniques developed for studies with rodents. Our knowledge of molecular and cellular mechanisms for ASD is mostly limited to what we have learned from genetically modified mice. However, there are significant evolutionary differences in brain structure and behavior between rodents and humans. For example, social behaviors and the organization of cerebral cortex differ significantly between primates and rodents. The cerebral neocortex comprises ~80% of the human brain and ~72% of the macaque brain, but only ~28% of the rat brain. Prefrontal cortex (PFC), a critical region for high order cognitive and social functions, is under-developed in rodents compared with primates. The unique behavioral features in human ASD have posed significant challenges to assess the translational value of many findings from ASD mouse models. The apparent evolutionary differences in brain structures and behaviors between mouse and human highlight the need of alternative animal models such as non-human primate models for ASD3.

    更新日期:2017-10-18
  • Enhanced base editing by co-expression of free uracil DNA glycosylase inhibitor
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Lijie Wang, Wei Xue, Lei Yan, Xiaosa Li, Jia Wei, Miaomiao Chen, Jing Wu, Bei Yang, Li Yang, Jia Chen

    Base editors (BEs) have been recently developed by combining the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like)/AID (activation-induced deaminase) cytidine deaminase family members1 with the CRISPR/Cas9 system to perform targeted C-to-T base editing2, 3, 4, 5,6,7,8. Mechanistically, Cas9 variant-fused APOBEC/AID is directed to target site by sgRNA, introducing C-to-T substitution at the single-base level2,3,4. Compared to earlier generations of BEs (BE1 and BE2), the latest BE3 achieved much higher base editing frequencies by substituting catalytically-dead Cas9 (dCas9) with Cas9 nickase (nCas9)2.

    更新日期:2017-10-18
  • Cryo-EM structures of the 80S ribosomes from human parasites Trichomonas vaginalis and Toxoplasma gondii
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Zhifei Li, Qiang Guo, Lvqin Zheng, Yongsheng Ji, Yi-Ting Xie, De-Hua Lai, Zhao-Rong Lun, Xun Suo, Ning Gao

    As an indispensable molecular machine universal in all living organisms, the ribosome has been selected by evolution to be the natural target of many antibiotics and small-molecule inhibitors. High-resolution structures of pathogen ribosomes are crucial for understanding the general and unique aspects of translation control in disease-causing microbes. With cryo-electron microscopy technique, we have determined structures of the cytosolic ribosomes from two human parasites, Trichomonas vaginalis and Toxoplasma gondii, at resolution of 3.2–3.4 Å. Although the ribosomal proteins from both pathogens are typical members of eukaryotic families, with a co-evolution pattern between certain species-specific insertions/extensions and neighboring ribosomal RNA (rRNA) expansion segments, the sizes of their rRNAs are sharply different. Very interestingly, rRNAs of T. vaginalis are in size comparable to prokaryotic counterparts, with nearly all the eukaryote-specific rRNA expansion segments missing. These structures facilitate the dissection of evolution path for ribosomal proteins and RNAs, and may aid in design of novel translation inhibitors.

    更新日期:2017-10-18
  • Genome-wide identification of histone H2A and histone variant H2A.Z-interacting proteins by bPPI-seq
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Yi Zhang, Wai Lim Ku, Shuai Liu, Kairong Cui, Wenfei Jin, Qingsong Tang, William Lu, Bing Ni, Keji Zhao

    H2A is a nucleosome core subunit involved in organizing DNA into a chromatin structure that is often inaccessible to regulatory enzymes. Replacement of H2A by its variant H2A.Z renders chromatin accessible at enhancers and promoters. However, it remains unclear how H2A.Z functions so differently from canonical H2A. Here we report the genome-wide identification of proteins that directly interact with H2A and H2A.Z in vivo using a novel strategy, bPPI-seq. We show that bPPI-seq is a sensitive and robust technique to identify protein-protein interactions in vivo. Our data indicate that H2A.Z-interacting proteins and H2A-interacting proteins participate in distinct biological processes. In contrast to H2A-interacting proteins, the H2A.Z-interacting proteins are involved in transcriptional regulation. We found that the transcription factor Osr1 interacts with H2A.Z both in vitro and in vivo. It also mediates H2A.Z incorporation to a large number of target sites and regulates gene expression. Our data indicate that bPPI-seq can be widely applied to identify genome-wide interacting proteins under physiological conditions.

    更新日期:2017-10-18
  • 5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Wenshuai Li, Xu Zhang, Xingyu Lu, Lei You, Yanqun Song, Zhongguang Luo, Jun Zhang, Ji Nie, Wanwei Zheng, Diannan Xu, Yaping Wang, Yuanqiang Dong, Shulin Yu, Jun Hong, Jianping Shi, Hankun Hao, Fen Luo, Luchun Hua, Peng Wang, Xiaoping Qian, Fang Yuan, Lianhuan Wei, Ming Cui, Taiping Zhang, Quan Liao, Menghua Dai, Ziwen Liu, Ge Chen, Katherine Meckel, Sarbani Adhikari, Guifang Jia, Marc B Bissonnette, Xinxiang Zhang, Yupei Zhao, Wei Zhang, Chuan He, Jie Liu

    DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here the genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and in genomic DNA (gDNA) of paired tumor and adjacent tissues collected from a cohort of 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver or thyroid cancer and normal tissues from 90 healthy individuals. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures were identified in cfDNA that were characteristic for specific cancer types. 5hmC-based biomarkers of circulating cfDNA were highly predictive of colorectal and gastric cancers and were superior to conventional biomarkers and comparable to 5hmC biomarkers from tissue biopsies. Thus, this new strategy could lead to the development of effective, minimally invasive methods for diagnosis and prognosis of cancer from the analyses of blood samples.

    更新日期:2017-10-18
  • 5-Hydroxymethylcytosine signatures in cell-free DNA provide information about tumor types and stages
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Chun-Xiao Song, Senlin Yin, Li Ma, Amanda Wheeler, Yu Chen, Yan Zhang, Bin Liu, Junjie Xiong, Weihan Zhang, Jiankun Hu, Zongguang Zhou, Biao Dong, Zhiqi Tian, Stefanie S Jeffrey, Mei-Sze Chua, Samuel So, Weimin Li, Yuquan Wei, Jiajie Diao, Dan Xie, Stephen R Quake

    5-Hydroxymethylcytosine (5hmC) is an important mammalian DNA epigenetic modification that has been linked to gene regulation and cancer pathogenesis. Here we explored the diagnostic potential of 5hmC in circulating cell-free DNA (cfDNA) using a sensitive chemical labeling-based low-input shotgun sequencing approach. We sequenced cell-free 5hmC from 49 patients of seven different cancer types and found distinct features that could be used to predict cancer types and stages with high accuracy. Specifically, we discovered that lung cancer leads to a progressive global loss of 5hmC in cfDNA, whereas hepatocellular carcinoma and pancreatic cancer lead to disease-specific changes in the cell-free hydroxymethylome. Our proof-of-principle results suggest that cell-free 5hmC signatures may potentially be used not only to identify cancer types but also to track tumor stage in some cancers.

    更新日期:2017-10-18
  • Mettl3-/Mettl14-mediated mRNA N6-methyladenosine modulates murine spermatogenesis
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Zhen Lin, Phillip J Hsu, Xudong Xing, Jianhuo Fang, Zhike Lu, Qin Zou, Ke-Jia Zhang, Xiao Zhang, Yuchuan Zhou, Teng Zhang, Youcheng Zhang, Wanlu Song, Guifang Jia, Xuerui Yang, Chuan He, Ming-Han Tong

    Spermatogenesis is a differentiation process during which diploid spermatogonial stem cells (SSCs) produce haploid spermatozoa. This highly specialized process is precisely controlled at the transcriptional, posttranscriptional, and translational levels. Here we report that N6-methyladenosine (m6A), an epitranscriptomic mark regulating gene expression, plays essential roles during spermatogenesis. We present comprehensive m6A mRNA methylomes of mouse spermatogenic cells from five developmental stages: undifferentiated spermatogonia, type A1 spermatogonia, preleptotene spermatocytes, pachytene/diplotene spermatocytes, and round spermatids. Germ cell-specific inactivation of the m6A RNA methyltransferase Mettl3 or Mettl14 with Vasa-Cre causes loss of m6A and depletion of SSCs. m6A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation. Combined deletion of Mettl3 and Mettl14 in advanced germ cells with Stra8-GFPCre disrupts spermiogenesis, whereas mice with single deletion of either Mettl3 or Mettl14 in advanced germ cells show normal spermatogenesis. The spermatids from double-mutant mice exhibit impaired translation of haploid-specific genes that are essential for spermiogenesis. This study highlights crucial roles of mRNA m6A modification in germline development, potentially ensuring coordinated translation at different stages of spermatogenesis.

    更新日期:2017-10-18
  • Cardiotrophin 1 stimulates beneficial myogenic and vascular remodeling of the heart
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Mohammad Abdul-Ghani, Colin Suen, Baohua Jiang, Yupu Deng, Jonathan J Weldrick, Charis Putinski, Steve Brunette, Pasan Fernando, Tom T Lee, Peter Flynn, Frans H H Leenen, Patrick G Burgon, Duncan J Stewart, Lynn A Megeney

    The post-natal heart adapts to stress and overload through hypertrophic growth, a process that may be pathologic or beneficial (physiologic hypertrophy). Physiologic hypertrophy improves cardiac performance in both healthy and diseased individuals, yet the mechanisms that propagate this favorable adaptation remain poorly defined. We identify the cytokine cardiotrophin 1 (CT1) as a factor capable of recapitulating the key features of physiologic growth of the heart including transient and reversible hypertrophy of the myocardium, and stimulation of cardiomyocyte-derived angiogenic signals leading to increased vascularity. The capacity of CT1 to induce physiologic hypertrophy originates from a CK2-mediated restraining of caspase activation, preventing the transition to unrestrained pathologic growth. Exogenous CT1 protein delivery attenuated pathology and restored contractile function in a severe model of right heart failure, suggesting a novel treatment option for this intractable cardiac disease.

    更新日期:2017-10-18
  • Coding GPCR-G protein specificity
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Sebastian GB Furness, Patrick M Sexton

    G protein-coupled receptors (GPCRs) are ubiquitous gatekeepers of cellular response and signal predominantly by recruitment and activation of G proteins. In a recent paper in Nature, Flock et al. use large-scale bioinformatics to build a model of GPCR-G protein selectivity and an interactive database to interrogate potential receptor-G protein interactions.

    更新日期:2017-10-18
  • IPA1: a direct target of SL signaling
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Stephanie C Kerr, Christine A Beveridge

    The plant hormone strigolactone (SL) is important for many processes in plants, but its molecular mode of action has been difficult to elucidate. A new discovery has identified the SPL transcription factor, IPA1, as a crucial component directly involved in SL signaling.

    更新日期:2017-10-18
  • New path towards a better rice architecture
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    Reynante L Ordonio, Makoto Matsuoka

    New plant type (NPT) or ideal plant architecture (IPA) is an attractive way of increasing yield potential by promoting high resource use efficiency combined with better lodging resistance. In a recent paper in Cell Research, Wang et al. describe how a QTL they identified could bring about the desired NPT architecture by elucidating the role of its encoded gene in controlling the stability of IPA1/OsSPL14, a previously reported NPT protein, in the context of ubiquitination.

    更新日期:2017-10-18
  • Size matters: Finding growth pathways that protect the heart
    Cell Res. (IF 15.606) Pub Date : 2017-10-18
    J Sawalla Guseh, Anthony Rosenzweig

    In a recent paper published in Cell Research, Abdul-Ghani and colleagues show that the cytokine, cardiotrophin-1 (CT1), drives a protective form of reversible cardiac hypertrophy that acts through a nonapoptotic caspase-dependent mechanism. Since CT1 can be delivered as exogenous protein, these studies provide new biological insights and potential translational opportunities.

    更新日期:2017-10-18
  • Structural and mechanistic insights into the biosynthesis of CDP-archaeol in membranes
    Cell Res. (IF 15.606) Pub Date : 2017-09-29
    Sixue Ren, Antonella Caforio, Qin Yang, Bo Sun, Feng Yu, Xiaofeng Zhu, Jinjing Wang, Chao Dou, Qiuyu Fu, Niu Huang, Qiu Sun, Chunlai Nie, Shiqian Qi, Xinqi Gong, Jianhua He, Yuquan Wei, Arnold JM Driessen, Wei Cheng

    The divergence of archaea, bacteria and eukaryotes was a fundamental step in evolution. One marker of this event is a major difference in membrane lipid chemistry between these kingdoms. Whereas the membranes of bacteria and eukaryotes primarily consist of straight fatty acids ester-bonded to glycerol-3-phosphate, archaeal phospholipids consist of isoprenoid chains ether-bonded to glycerol-1-phosphate. Notably, the mechanisms underlying the biosynthesis of these lipids remain elusive. Here, we report the structure of the CDP-archaeol synthase (CarS) of Aeropyrum pernix (ApCarS) in the CTP- and Mg2+-bound state at a resolution of 2.4 Å. The enzyme comprises a transmembrane domain with five helices and cytoplasmic loops that together form a large charged cavity providing a binding site for CTP. Identification of the binding location of CTP and Mg2+ enabled modeling of the specific lipophilic substrate-binding site, which was supported by site-directed mutagenesis, substrate-binding affinity analyses, and enzyme assays. We propose that archaeol binds within two hydrophobic membrane-embedded grooves formed by the flexible transmembrane helix 5 (TM5), together with TM1 and TM4. Collectively, structural comparisons and analyses, combined with functional studies, not only elucidated the mechanism governing the biosynthesis of phospholipids with ether-bonded isoprenoid chains by CTP transferase, but also provided insights into the evolution of this enzyme superfamily from archaea to bacteria and eukaryotes.

    更新日期:2017-10-10
  • Structural step forward for NHEJ
    Cell Res. (IF 15.606) Pub Date : 2017-09-19
    Go Watanabe, Michael R Lieber, Dewight Williams

    In a recent paper published in Cell Research, a cryo-EM structure reveals the interface between DNA-PKcs and the Ku70/80:DNA complex, together forming the DNA-dependent protein kinase holoenzyme in non-homologous DNA end joining. Insight from this structure suggests how an allosteric rearrangement of DNA-PKcs driven by Ku70/80:DNA binding regulates kinase activity in this largest member of a family of structurally homologous phosphoinositide 3-kinase-related protein kinases that includes mTOR, ATR, and ATM.

    更新日期:2017-09-22
  • 5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers
    Cell Res. (IF 15.606) Pub Date : 2017-09-19
    Wenshuai Li, Xu Zhang, Xingyu Lu, Lei You, Yanqun Song, Zhongguang Luo, Jun Zhang, Ji Nie, Wanwei Zheng, Diannan Xu, Yaping Wang, Yuanqiang Dong, Shulin Yu, Jun Hong, Jianping Shi, Hankun Hao, Fen Luo, Luchun Hua, Peng Wang, Xiaoping Qian, Fang Yuan, Lianhuan Wei, Ming Cui, Taiping Zhang, Quan Liao, Menghua Dai, Ziwen Liu, Ge Chen, Katherine Meckel, Sarbani Adhikari, Guifang Jia, Marc B Bissonnette, Xinxiang Zhang, Yupei Zhao, Wei Zhang, Chuan He, Jie Liu

    DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here the genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and in genomic DNA (gDNA) of paired tumor and adjacent tissues collected from a cohort of 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver or thyroid cancer and normal tissues from 90 healthy individuals. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures were identified in cfDNA that were characteristic for specific cancer types. 5hmC-based biomarkers of circulating cfDNA were highly predictive of colorectal and gastric cancers and were superior to conventional biomarkers and comparable to 5hmC biomarkers from tissue biopsies. Thus, this new strategy could lead to the development of effective, minimally invasive methods for diagnosis and prognosis of cancer from the analyses of blood samples.

    更新日期:2017-09-22
  • Size matters: Finding growth pathways that protect the heart
    Cell Res. (IF 15.606) Pub Date : 2017-09-19
    J Sawalla Guseh, Anthony Rosenzweig

    In a recent paper published in Cell Research, Abdul-Ghani and colleagues show that the cytokine, cardiotrophin-1 (CT1), drives a protective form of reversible cardiac hypertrophy that acts through a nonapoptotic caspase-dependent mechanism. Since CT1 can be delivered as exogenous protein, these studies provide new biological insights and potential translational opportunities.

    更新日期:2017-09-22
  • A vital sugar code for ricin toxicity
    Cell Res. (IF 15.606) Pub Date : 2017-09-19
    Jasmin Taubenschmid, Johannes Stadlmann, Markus Jost, Tove Irene Klokk, Cory D Rillahan, Andreas Leibbrandt, Karl Mechtler, James C Paulson, Julian Jude, Johannes Zuber, Kirsten Sandvig, Ulrich Elling, Thorsten Marquardt, Christian Thiel, Christian Koerner, Josef M Penninger

    Ricin is one of the most feared bioweapons in the world due to its extreme toxicity and easy access. Since no antidote exists, it is of paramount importance to identify the pathways underlying ricin toxicity. Here, we demonstrate that the Golgi GDP-fucose transporter Slc35c1 and fucosyltransferase Fut9 are key regulators of ricin toxicity. Genetic and pharmacological inhibition of fucosylation renders diverse cell types resistant to ricin via deregulated intracellular trafficking. Importantly, cells from a patient with SLC35C1 deficiency are also resistant to ricin. Mechanistically, we confirm that reduced fucosylation leads to increased sialylation of Lewis X structures and thus masking of ricin-binding sites. Inactivation of the sialyltransferase responsible for modifications of Lewis X (St3Gal4) increases the sensitivity of cells to ricin, whereas its overexpression renders cells more resistant to the toxin. Thus, we have provided unprecedented insights into an evolutionary conserved modular sugar code that can be manipulated to control ricin toxicity.

    更新日期:2017-09-22
  • New path towards a better rice architecture
    Cell Res. (IF 15.606) Pub Date : 2017-09-12
    Reynante L Ordonio, Makoto Matsuoka

    New plant type (NPT) or ideal plant architecture (IPA) is an attractive way of increasing yield potential by promoting high resource use efficiency combined with better lodging resistance. In a recent paper in Cell Research, Wang et al. describe how a QTL they identified could bring about the desired NPT architecture by elucidating the role of its encoded gene in controlling the stability of IPA1/OsSPL14, a previously reported NPT protein, in the context of ubiquitination.

    更新日期:2017-09-15
  • Enhanced base editing by co-expression of free uracil DNA glycosylase inhibitor
    Cell Res. (IF 15.606) Pub Date : 2017-08-29
    Lijie Wang, Wei Xue, Lei Yan, Xiaosa Li, Jia Wei, Miaomiao Chen, Jing Wu, Bei Yang, Li Yang, Jia Chen

    Base editors (BEs) have been recently developed by combining the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like)/AID (activation-induced deaminase) cytidine deaminase family members1 with the CRISPR/Cas9 system to perform targeted C-to-T base editing2, 3, 4, 5,6,7,8. Mechanistically, Cas9 variant-fused APOBEC/AID is directed to target site by sgRNA, introducing C-to-T substitution at the single-base level2,3,4. Compared to earlier generations of BEs (BE1 and BE2), the latest BE3 achieved much higher base editing frequencies by substituting catalytically-dead Cas9 (dCas9) with Cas9 nickase (nCas9)2.

    更新日期:2017-08-31
  • RIPped for neuroinflammation
    Cell Res. (IF 15.606) Pub Date : 2017-08-24
    Bart Tummers, Douglas R Green

    Activation of the receptor interacting serine/threonine kinase (RIPK) 3 mediates an inflammatory type of cell death called necroptosis; in addition, RIPK3 has necroptosis-independent roles in inflammation, although these are not well defined. In a recent study published in Cell, Daniels and colleagues demonstrate that RIPK3 controls West Nile virus infection by promoting neuroinflammation in the central nervous system without affecting neuronal death.

    更新日期:2017-08-25
  • YAP activates the Hippo pathway in a negative feedback loop
    Cell Res. (IF 15.606) Pub Date : 2017-08-24
    Xiaoming Dai, Huan Liu, Shuying Shen, Xiaocan Guo, Huan Yan, Xinyan Ji, Li Li, Jun Huang, Xin-Hua Feng, Bin Zhao

    10.1038/cr.2017.96

    更新日期:2017-08-25
  • Fibroblasts in an endocardial fibroelastosis disease model mainly originate from mesenchymal derivatives of epicardium
    Cell Res. (IF 15.606) Pub Date : 2017-08-15
    Hui Zhang, Xiuzhen Huang, Kuo Liu, Juan Tang, Lingjuan He, Wenjuan Pu, Qiaozhen Liu1,2, Yan Li, Xueying Tian, Yue Wang, Libo Zhang, Ying Yu, Hongyan Wang, Ronggui Hu, Fengchao Wang, Ting Chen, Qing-Dong Wang, Zengyong Qiao, Li Zhang, Kathy O Lui8 and Bin Zhou

    Endocardial fibroelastosis (EFE) refers to the thickening of the ventricular endocardium as a result of de novo deposition of subendocardial fibrous tissue layers during neonatal heart development. The origin of EFE fibroblasts is proposed to be postnatal endocardial cells that undergo an aberrant endothelial-to-mesenchymal transition (EndMT). Genetic lineage tracing of endocardial cells with the inducible endocardial Cre line Npr3-CreER and the endothelial cell tracing line Cdh5-CreER on an EFE-like model did not reveal any contribution of neonatal endocardial cells to fibroblasts in the EFE-like tissues. Instead, lineage tracing of embryonic epicardium by Wt1-CreER suggested that epicardium-derived mesenchymal cells (MCs) served as the major source of EFE fibroblasts. By labeling MCs using Sox9-CreER, we confirmed that MCs of the embryonic heart expand and contribute to the majority of neonatal EFE fibroblasts. During this pathological process, TGFβ signaling, the key mediator of fibroblasts activation, was highly upregulated in the EFE-like tissues. Targeting TGFβ signaling by administration of its antagonist bone morphogenetic protein 7 effectively reduced fibroblast accumulation and tissue fibrosis in the EFE-like model. Our study provides genetic evidence that excessive fibroblasts in the EFE-like tissues mainly originate from the epicardium-derived MCs through epicardial to mesenchymal transition (EpiMT). These EpiMT-derived fibroblasts within the EFE-like tissues could serve as a potential therapeutic target.

    更新日期:2017-08-18
  • Mettl3-mediated m6A regulates spermatogonial differentiation and meiosis initiation
    Cell Res. (IF 15.606) Pub Date : 2017-08-15
    Kai Xu, Ying Yang, Gui-Hai Feng, Bao-Fa Sun, Jun-Qing Chen, Yu-Fei Li, Yu-Sheng Chen, Xin-Xin Zhang, Chen-Xin Wang, Li-Yuan Jiang, Chao Liu, Ze-Yu Zhang, Xiu-Jie Wang, Qi Zhou, Yun-Gui Yang, Wei Li

    METTL3 catalyzes the formation of N6-methyl-adenosine (m6A) which has important roles in regulating various biological processes. However, the in vivo function of Mettl3 remains largely unknown in mammals. Here we generated germ cell-specific Mettl3 knockout mice and demonstrated that Mettl3 was essential for male fertility and spermatogenesis. The ablation of Mettl3 in germ cells severely inhibited spermatogonial differentiation and blocked the initiation of meiosis. Transcriptome and m6A profiling analysis revealed that genes functioning in spermatogenesis had altered profiles of expression and alternative splicing. Our findings provide novel insights into the function and regulatory mechanisms of Mettl3-mediated m6A modification in spermatogenesis and reproduction in mammals.

    更新日期:2017-08-18
  • IPA1 functions as a downstream transcription factor repressed by D53 in strigolactone signaling in rice
    Cell Res. (IF 15.606) Pub Date : 2017-08-15
    Xiaoguang Song, Zefu Lu, Hong Yu, Gaoneng Shao, Jinsong Xiong, Xiangbing Meng, Yanhui Jing, Guifu Liu, Guosheng Xiong, Jingbo Duan, Xue-Feng Yao, Chun-Ming Liu, Hongqing Li, Yonghong Wang, Jiayang Li

    Strigolactones (SLs), a group of carotenoid derived terpenoid lactones, are root-to-shoot phytohormones suppressing shoot branching by inhibiting the outgrowth of axillary buds. DWARF 53 (D53), the key repressor of the SL signaling pathway, is speculated to regulate the downstream transcriptional network of the SL response. However, no downstream transcription factor targeted by D53 has yet been reported. Here we report that Ideal Plant Architecture 1 (IPA1), a key regulator of the plant architecture in rice, functions as a direct downstream component of D53 in regulating tiller number and SL-induced gene expression. We showed that D53 interacts with IPA1 in vivo and in vitro and suppresses the transcriptional activation activity of IPA1. We further showed that IPA1 could directly bind to the D53 promoter and plays a critical role in the feedback regulation of SL-induced D53 expression. These findings reveal that IPA1 is likely one of the long-speculated transcription factors that act with D53 to mediate the SL-regulated tiller development in rice.

    更新日期:2017-08-18
  • Cryo-EM structures of the 80S ribosomes from human parasites Trichomonas vaginalis and Toxoplasma gondii
    Cell Res. (IF 15.606) Pub Date : 2017-08-15
    Zhifei Li, Qiang Guo, Lvqin Zheng, Yongsheng Ji, Yi-Ting Xie, De-Hua Lai, Zhao-Rong Lun, Xun Suo, Ning Gao

    As an indispensable molecular machine universal in all living organisms, the ribosome has been selected by evolution to be the natural target of many antibiotics and small-molecule inhibitors. High-resolution structures of pathogen ribosomes are crucial for understanding the general and unique aspects of translation control in disease-causing microbes. With cryo-electron microscopy technique, we have determined structures of the cytosolic ribosomes from two human parasites, Trichomonas vaginalis and Toxoplasma gondii, at resolution of 3.2–3.4 Å. Although the ribosomal proteins from both pathogens are typical members of eukaryotic families, with a co-evolution pattern between certain species-specific insertions/extensions and neighboring ribosomal RNA (rRNA) expansion segments, the sizes of their rRNAs are sharply different. Very interestingly, rRNAs of T. vaginalis are in size comparable to prokaryotic counterparts, with nearly all the eukaryote-specific rRNA expansion segments missing. These structures facilitate the dissection of evolution path for ribosomal proteins and RNAs, and may aid in design of novel translation inhibitors.

    更新日期:2017-08-18
  • SMAD5 signaling: more than meets the nuclei
    Cell Res. (IF 15.606) Pub Date : 2017-08-15
    John Orlowski

    SMADs are essential transcriptional effectors of transforming growth factor-β (TGFβ)/TGFβ-related signaling that underlies embryonic development and adult homeostasis. A recent study by Fang et al. in Cell Research adds to this biological complexity by demonstrating an atypical cytoplasmic role for SMAD5 in modulating the bioenergetic homeostasis (i.e., glycolysis and mitochondrial respiration) of cells in response to fluctuations in intracellular pH that is independent of receptor signaling.

    更新日期:2017-08-18
  • Ythdc2 is an N 6-methyladenosine binding protein that regulates mammalian spermatogenesis
    Cell Res. (IF 15.606) Pub Date : 2017-08-15
    Phillip J Hsu, Yunfei Zhu, Honghui Ma, Yueshuai Guo, Xiaodan Shi, Yuanyuan Liu, Meijie Qi, Zhike Lu, Hailing Shi, Jianying Wang, Yiwei Cheng, Guanzheng Luo, Qing Dai, Mingxi Liu, Xuejiang Guo, Jiahao Sha, Bin Shen, Chuan He

    N6-methyladenosine (m6A) is the most common internal modification in eukaryotic mRNA. It is dynamically installed and removed, and acts as a new layer of mRNA metabolism, regulating biological processes including stem cell pluripotency, cell differentiation, and energy homeostasis. m6A is recognized by selective binding proteins; YTHDF1 and YTHDF3 work in concert to affect the translation of m6A-containing mRNAs, YTHDF2 expedites mRNA decay, and YTHDC1 affects the nuclear processing of its targets. The biological function of YTHDC2, the final member of the YTH protein family, remains unknown. We report that YTHDC2 selectively binds m6A at its consensus motif. YTHDC2 enhances the translation efficiency of its targets and also decreases their mRNA abundance. Ythdc2 knockout mice are infertile; males have significantly smaller testes and females have significantly smaller ovaries compared to those of littermates. The germ cells of Ythdc2 knockout mice do not develop past the zygotene stage and accordingly, Ythdc2 is upregulated in the testes as meiosis begins. Thus, YTHDC2 is an m6A-binding protein that plays critical roles during spermatogenesis.

    更新日期:2017-08-18
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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