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  • MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-18
    Yves Dondelinger, Tom Delanghe, Diego Rojas-Rivera, Dario Priem, Tinneke Delvaeye, Inge Bruggeman, Franky Van Herreweghe, Peter Vandenabeele, Mathieu J. M. Bertrand

    Dondelinger et al. and Menon et al. show that MAPKAP kinase-2 (MK2) phosphorylates RIPK1 to regulate TNF-mediated cell death as well as RIPK1 signalling in inflammation and bacterial infection.

    更新日期:2017-09-18
  • Lifelong haematopoiesis is established by hundreds of precursors throughout mammalian ontogeny
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-18
    Miguel Ganuza, Trent Hall, David Finkelstein, Ashley Chabot, Guolian Kang, Shannon McKinney-Freeman

    Ganuza et al. track newly specified blood progenitors in the dorsal aorta of the mouse embryo and demonstrate that they are polyclonal in origin and that hundreds of mesodermal, endothelial and blood precursors establish lifelong haematopoiesis.

    更新日期:2017-09-18
  • p38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-18
    Manoj B. Menon, Julia Gropengießer, Jessica Fischer, Lena Novikova, Anne Deuretzbacher, Juri Lafera, Hanna Schimmeck, Nicole Czymmeck, Natalia Ronkina, Alexey Kotlyarov, Martin Aepfelbacher, Matthias Gaestel, Klaus Ruckdeschel

    Dondelinger et al. and Menon et al. show that MAPKAP kinase-2 (MK2) phosphorylates RIPK1 to regulate TNF-mediated cell death as well as RIPK1 signalling in inflammation and bacterial infection.

    更新日期:2017-09-18
  • miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-18
    Min-Zu Wu, Wei-Chung Cheng, Su-Feng Chen, Shin Nieh, Carolyn O’Connor, Chia-Lin Liu, Wen-Wei Tsai, Cheng-Jang Wu, Lorena Martin, Yaoh-Shiang Lin, Kou-Juey Wu, Li-Fan Lu, Juan Carlos Izpisua Belmonte

    Wu et al. found that tumour hypoxic conditions increase miR25/93 levels, which via targeting Ncoa3 downregulate the expression of the innate immune regulator cGAS, thus allowing escape of the anti-tumour immune response.

    更新日期:2017-09-18
  • A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-11
    Ji-Hyung Lee, Su Myung Jung, Kyung-Min Yang, Eunjin Bae, Sung Gwe Ahn, Jin Seok Park, Dongyeob Seo, Minbeom Kim, Jihoon Ha, Jaewon Lee, Jun-Hyeong Kim, Jun Hwan Kim, Akira Ooshima, Jinah Park, Donghyuk Shin, Youn Sook Lee, Sangho Lee, Geert van Loo, Joon Jeong, Seong-Jin Kim, Seok Hee Park

    Although the ubiquitin-editing enzyme A20 is a key player in inflammation and autoimmunity, its role in cancer metastasis remains unknown. Here we show that A20 monoubiquitylates Snail1 at three lysine residues and thereby promotes metastasis of aggressive basal-like breast cancers. A20 is significantly upregulated in human basal-like breast cancers and its expression level is inversely correlated with metastasis-free patient survival. A20 facilitates TGF-β1-induced epithelial–mesenchymal transition (EMT) of breast cancer cells through multi-monoubiquitylation of Snail1. Monoubiquitylated Snail1 has reduced affinity for glycogen synthase kinase 3β (GSK3β), and is thus stabilized in the nucleus through decreased phosphorylation. Knockdown of A20 or overexpression of Snail1 with mutation of the monoubiquitylated lysine residues into arginine abolishes lung metastasis in mouse xenograft and orthotopic breast cancer models, indicating that A20 and monoubiquitylated Snail1 are required for metastasis. Our findings uncover an essential role of the A20–Snail1 axis in TGF-β1-induced EMT and metastasis of basal-like breast cancers.

    更新日期:2017-09-11
  • Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-11
    Kerrie E. McNally, Rebecca Faulkner, Florian Steinberg, Matthew Gallon, Rajesh Ghai, David Pim, Paul Langton, Neil Pearson, Chris M. Danson, Heike Nägele, Lindsey L. Morris, Amika Singla, Brittany L. Overlee, Kate J. Heesom, Richard Sessions, Lawrence Banks, Brett M. Collins, Imre Berger, Daniel D. Billadeau, Ezra Burstein, Peter J. Cullen

    Following endocytosis into the endosomal network, integral membrane proteins undergo sorting for lysosomal degradation or are retrieved and recycled back to the cell surface. Here we describe the discovery of an ancient and conserved multiprotein complex that orchestrates cargo retrieval and recycling and, importantly, is biochemically and functionally distinct from the established retromer pathway. We have called this complex ‘retriever’; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. We establish that retriever associates with the cargo adaptor sorting nexin 17 (SNX17) and couples to CCC (CCDC93, CCDC22, COMMD) and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of α5β1 integrin. Through quantitative proteomic analysis, we identify over 120 cell surface proteins, including numerous integrins, signalling receptors and solute transporters, that require SNX17–retriever to maintain their surface levels. Our identification of retriever establishes a major endosomal retrieval and recycling pathway.

    更新日期:2017-09-11
  • Myofibril contraction and crosslinking drive nuclear movement to the periphery of skeletal muscle
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-11
    William Roman, João P. Martins, Filomena A. Carvalho, Raphael Voituriez, Jasmine V. G. Abella, Nuno C. Santos, Bruno Cadot, Michael Way, Edgar R. Gomes

    Nuclear movements are important for multiple cellular functions, and are driven by polarized forces generated by motor proteins and the cytoskeleton. During skeletal myofibre formation or regeneration, nuclei move from the centre to the periphery of the myofibre for proper muscle function. Centrally located nuclei are also found in different muscle disorders. Using theoretical and experimental approaches, we demonstrate that nuclear movement to the periphery of myofibres is mediated by centripetal forces around the nucleus. These forces arise from myofibril contraction and crosslinking that ‘zip’ around the nucleus in combination with tight regulation of nuclear stiffness by lamin A/C. In addition, an Arp2/3 complex containing Arpc5L together with γ-actin is required to organize desmin to crosslink myofibrils for nuclear movement. Our work reveals that centripetal forces exerted by myofibrils squeeze the nucleus to the periphery of myofibres.

    更新日期:2017-09-11
  • Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-09-11
    Xueqian Zhuang, Hao Zhang, Xiaoyan Li, Xiaoxun Li, Min Cong, Fangli Peng, Jingyi Yu, Xue Zhang, Qifeng Yang, Guohong Hu

    Metastatic cancer is a systemic disease, and metastasis determinants might elicit completely different effects in various target organs. Here we show that tumour-secreted DKK1 is a serological marker of breast cancer metastasis organotropism and inhibits lung metastasis. DKK1 suppresses PTGS2-induced macrophage and neutrophil recruitment in lung metastases by antagonizing cancer cell non-canonical WNT/PCP–RAC1–JNK signalling. In the lungs, DKK1 also inhibits WNT/Ca2+–CaMKII–NF-κB signalling and suppresses LTBP1-mediated TGF-β secretion of cancer cells. In contrast, DKK1 promotes breast-to-bone metastasis by regulating canonical WNT signalling of osteoblasts. Importantly, targeting canonical WNT may not be beneficial to treatment of metastatic cancer, while combinatory therapy against JNK and TGF-β signalling effectively prevents metastasis to both the lungs and bone. Thus, DKK1 represents a class of Janus-faced molecules with dichotomous roles in organotropic metastasis, and our data provide a rationale for new anti-metastasis approaches.

    更新日期:2017-09-11
  • Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-28
    Evangelos Giampazolias, Barbara Zunino, Sandeep Dhayade, Florian Bock, Catherine Cloix, Kai Cao, Alba Roca, Jonathan Lopez, Gabriel Ichim, Emma Proïcs, Camila Rubio-Patiño, Loic Fort, Nader Yatim, Emma Woodham, Susana Orozco, Lucia Taraborrelli, Nieves Peltzer, Daniele Lecis, Laura Machesky, Henning Walczak, Matthew L. Albert, Simon Milling, Andrew Oberst, Jean-Ehrland Ricci, Kevin M. Ryan, Karen Blyth, Stephen W. G. Tait

    Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies.

    更新日期:2017-09-07
  • Reversible protein aggregation is a protective mechanism to ensure cell cycle restart after stress
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-28
    Shady Saad, Gea Cereghetti, Yuehan Feng, Paola Picotti, Matthias Peter, Reinhard Dechant

    Protein aggregation is mostly viewed as deleterious and irreversible causing several pathologies. However, reversible protein aggregation has recently emerged as a novel concept for cellular regulation. Here, we characterize stress-induced, reversible aggregation of yeast pyruvate kinase, Cdc19. Aggregation of Cdc19 is regulated by oligomerization and binding to allosteric regulators. We identify a region of low compositional complexity (LCR) within Cdc19 as necessary and sufficient for reversible aggregation. During exponential growth, shielding the LCR within tetrameric Cdc19 or phosphorylation of the LCR prevents unscheduled aggregation, while its dephosphorylation is necessary for reversible aggregation during stress. Cdc19 aggregation triggers its localization to stress granules and modulates their formation and dissolution. Reversible aggregation protects Cdc19 from stress-induced degradation, thereby allowing cell cycle restart after stress. Several other enzymes necessary for G1 progression also contain LCRs and aggregate reversibly during stress, implying that reversible aggregation represents a conserved mechanism regulating cell growth and survival.

    更新日期:2017-09-07
  • Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-28
    Xiaoyu Shi, Galo Garcia III, Julie C. Van De Weghe, Ryan McGorty, Gregory J. Pazour, Dan Doherty, Bo Huang, Jeremy F. Reiter

    Ciliopathies, including nephronophthisis (NPHP), Meckel syndrome (MKS) and Joubert syndrome (JBTS), can be caused by mutations affecting components of the transition zone, a domain near the base of the cilium that controls the protein composition of its membrane. We defined the three-dimensional arrangement of key proteins in the transition zone using two-colour stochastic optical reconstruction microscopy (STORM). NPHP and MKS complex components form nested rings comprised of nine-fold doublets. JBTS-associated mutations in RPGRIP1L or TCTN2 displace certain transition-zone proteins. Diverse ciliary proteins accumulate at the transition zone in wild-type cells, suggesting that the transition zone is a waypoint for proteins entering and exiting the cilium. JBTS-associated mutations in RPGRIP1L disrupt SMO accumulation at the transition zone and the ciliary localization of SMO. We propose that the disruption of transition-zone architecture in JBTS leads to a failure of SMO to accumulate at the transition zone and cilium, disrupting developmental signalling in JBTS.

    更新日期:2017-09-07
  • ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-28
    Maria Skamagki, Cristina Correia, Percy Yeung, Timour Baslan, Samuel Beck, Cheng Zhang, Christian A. Ross, Lam Dang, Zhong Liu, Simona Giunta, Tzu-Pei Chang, Joye Wang, Aparna Ananthanarayanan, Martina Bohndorf, Benedikt Bosbach, James Adjaye, Hironori Funabiki, Jonghwan Kim, Scott Lowe, James J. Collins, Chi-Wei Lu, Hu Li, Rui Zhao, Kitai Kim

    Induced pluripotent stem cells (iPSCs), which are used to produce transplantable tissues, may particularly benefit older patients, who are more likely to suffer from degenerative diseases. However, iPSCs generated from aged donors (A-iPSCs) exhibit higher genomic instability, defects in apoptosis and a blunted DNA damage response compared with iPSCs generated from younger donors. We demonstrated that A-iPSCs exhibit excessive glutathione-mediated reactive oxygen species (ROS) scavenging activity, which blocks the DNA damage response and apoptosis and permits survival of cells with genomic instability. We found that the pluripotency factor ZSCAN10 is poorly expressed in A-iPSCs and addition of ZSCAN10 to the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) during A-iPSC reprogramming normalizes ROS–glutathione homeostasis and the DNA damage response, and recovers genomic stability. Correcting the genomic instability of A-iPSCs will ultimately enhance our ability to produce histocompatible functional tissues from older patients’ own cells that are safe for transplantation.

    更新日期:2017-09-07
  • A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-21
    Simon Grelet, Laura A. Link, Breege Howley, Clémence Obellianne, Viswanathan Palanisamy, Vamsi K. Gangaraju, J. Alan Diehl, Philip H. Howe

    The contribution of lncRNAs to tumour progression and the regulatory mechanisms driving their expression are areas of intense investigation. Here, we characterize the binding of heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) to a nucleic acid structural element located in exon 12 of PNUTS (also known as PPP1R10) pre-RNA that regulates its alternative splicing. HnRNP E1 release from this structural element, following its silencing, nucleocytoplasmic translocation or in response to TGFβ, allows alternative splicing and generates a non-coding isoform of PNUTS. Functionally the lncRNA-PNUTS serves as a competitive sponge for miR-205 during epithelial–mesenchymal transition (EMT). In mesenchymal breast tumour cells and in breast tumour samples, the expression of lncRNA-PNUTS is elevated and correlates with levels of ZEB mRNAs. Thus, PNUTS is a bifunctional RNA encoding both PNUTS mRNA and lncRNA-PNUTS, each eliciting distinct biological functions. While PNUTS mRNA is ubiquitously expressed, lncRNA-PNUTS appears to be tightly regulated dependent on the status of hnRNP E1 and tumour context.

    更新日期:2017-09-07
  • Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-21
    Sarah J. Horton, George Giotopoulos, Haiyang Yun, Shabana Vohra, Olivia Sheppard, Rachael Bashford-Rogers, Mamunur Rashid, Alexandra Clipson, Wai-In Chan, Daniel Sasca, Loukia Yiangou, Hikari Osaki, Faisal Basheer, Paolo Gallipoli, Natalie Burrows, Ayşegül Erdem, Anastasiya Sybirna, Sarah Foerster, Wanfeng Zhao, Tonci Sustic, Anna Petrunkina Harrison, Elisa Laurenti, Jessica Okosun, Daniel Hodson, Penny Wright, Ken G. Smith, Patrick Maxwell, Jude Fitzgibbon, Ming Q. Du, David J. Adams, Brian J. P. Huntly

    Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies.

    更新日期:2017-09-07
  • SMC complexes differentially compact mitotic chromosomes according to genomic context
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-21
    Stephanie Andrea Schalbetter, Anton Goloborodko, Geoffrey Fudenberg, Jon-Matthew Belton, Catrina Miles, Miao Yu, Job Dekker, Leonid Mirny, Jonathan Baxter

    Structural maintenance of chromosomes (SMC) protein complexes are key determinants of chromosome conformation. Using Hi-C and polymer modelling, we study how cohesin and condensin, two deeply conserved SMC complexes, organize chromosomes in the budding yeast Saccharomyces cerevisiae. The canonical role of cohesin is to co-align sister chromatids, while condensin generally compacts mitotic chromosomes. We find strikingly different roles for the two complexes in budding yeast mitosis. First, cohesin is responsible for compacting mitotic chromosome arms, independently of sister chromatid cohesion. Polymer simulations demonstrate that this role can be fully accounted for through cis-looping of chromatin. Second, condensin is generally dispensable for compaction along chromosome arms. Instead, it plays a targeted role compacting the rDNA proximal regions and promoting resolution of peri-centromeric regions. Our results argue that the conserved mechanism of SMC complexes is to form chromatin loops and that distinct SMC-dependent looping activities are selectively deployed to appropriately compact chromosomes.

    更新日期:2017-09-07
  • An apical MRCK-driven morphogenetic pathway controls epithelial polarity
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-21
    Ceniz Zihni, Evi Vlassaks, Stephen Terry, Jeremy Carlton, Thomas King Chor Leung, Michael Olson, Franck Pichaud, Maria Susana Balda, Karl Matter

    Polarized epithelia develop distinct cell surface domains, with the apical membrane acquiring characteristic morphological features such as microvilli. Cell polarization is driven by polarity determinants including the evolutionarily conserved partitioning-defective (PAR) proteins that are separated into distinct cortical domains. PAR protein segregation is thought to be a consequence of asymmetric actomyosin contractions. The mechanism of activation of apically polarized actomyosin contractility is unknown. Here we show that the Cdc42 effector MRCK activates myosin-II at the apical pole to segregate aPKC–Par6 from junctional Par3, defining the apical domain. Apically polarized MRCK-activated actomyosin contractility is reinforced by cooperation with aPKC–Par6 downregulating antagonistic RhoA-driven junctional actomyosin contractility, and drives polarization of cytosolic brush border determinants and apical morphogenesis. MRCK-activated polarized actomyosin contractility is required for apical differentiation and morphogenesis in vertebrate epithelia and Drosophila photoreceptors. Our results identify an apical origin of actomyosin-driven morphogenesis that couples cytoskeletal reorganization to PAR polarity signalling.

    更新日期:2017-09-07
  • Lactate dehydrogenase activity drives hair follicle stem cell activation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-14
    Aimee Flores, John Schell, Abigail S. Krall, David Jelinek, Matilde Miranda, Melina Grigorian, Daniel Braas, Andrew C. White, Jessica L. Zhou, Nicholas A. Graham, Thomas Graeber, Pankaj Seth, Denis Evseenko, Hilary A. Coller, Jared Rutter, Heather R. Christofk, William E. Lowry

    Although normally dormant, hair follicle stem cells (HFSCs) quickly become activated to divide during a new hair cycle. The quiescence of HFSCs is known to be regulated by a number of intrinsic and extrinsic mechanisms. Here we provide several lines of evidence to demonstrate that HFSCs utilize glycolytic metabolism and produce significantly more lactate than other cells in the epidermis. Furthermore, lactate generation appears to be critical for the activation of HFSCs as deletion of lactate dehydrogenase (Ldha) prevented their activation. Conversely, genetically promoting lactate production in HFSCs through mitochondrial pyruvate carrier 1 (Mpc1) deletion accelerated their activation and the hair cycle. Finally, we identify small molecules that increase lactate production by stimulating Myc levels or inhibiting Mpc1 carrier activity and can topically induce the hair cycle. These data suggest that HFSCs maintain a metabolic state that allows them to remain dormant and yet quickly respond to appropriate proliferative stimuli.

    更新日期:2017-09-07
  • NFIA co-localizes with PPARγ and transcriptionally controls the brown fat gene program
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-14
    Yuta Hiraike, Hironori Waki, Jing Yu, Masahiro Nakamura, Kana Miyake, Gaku Nagano, Ryo Nakaki, Ken Suzuki, Hirofumi Kobayashi, Shogo Yamamoto, Wei Sun, Tomohisa Aoyama, Yusuke Hirota, Haruya Ohno, Kenji Oki, Masayasu Yoneda, Andrew P. White, Yu-Hua Tseng, Aaron M. Cypess, Therese J. Larsen, Naja Z. Jespersen, Camilla Scheele, Shuichi Tsutsumi, Hiroyuki Aburatani, Toshimasa Yamauchi, Takashi Kadowaki

    Brown fat dissipates energy as heat and protects against obesity. Here, we identified nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of brown-fat-specific open chromatin regions. NFIA and the master transcriptional regulator of adipogenesis, PPARγ, co-localize at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARγ, leading to increased chromatin accessibility and active transcription. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA-knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. Finally, expression of NFIA and the brown-fat-specific genes is positively correlated in human brown fat. These results indicate that NFIA activates the cell-type-specific enhancers and facilitates the binding of PPARγ to control the brown fat gene program.

    更新日期:2017-09-07
  • Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-14
    John C. Schell, Dona R. Wisidagama, Claire Bensard, Helong Zhao, Peng Wei, Jason Tanner, Aimee Flores, Jeffrey Mohlman, Lise K. Sorensen, Christian S. Earl, Kristofor A. Olson, Ren Miao, T. Cameron Waller, Don Delker, Priyanka Kanth, Lei Jiang, Ralph J. DeBerardinis, Mary P. Bronner, Dean Y. Li, James E. Cox, Heather R. Christofk, William E. Lowry, Carl S. Thummel, Jared Rutter

    Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells.

    更新日期:2017-09-07
  • Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-31
    Selene Glück, Baptiste Guey, Muhammet Fatih Gulen, Katharina Wolter, Tae-Won Kang, Niklas Arndt Schmacke, Anne Bridgeman, Jan Rehwinkel, Lars Zender, Andrea Ablasser

    Cellular senescence is triggered by various distinct stresses and characterized by a permanent cell cycle arrest. Senescent cells secrete a variety of inflammatory factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The mechanism(s) underlying the regulation of the SASP remains incompletely understood. Here we define a role for innate DNA sensing in the regulation of senescence and the SASP. We find that cyclic GMP-AMP synthase (cGAS) recognizes cytosolic chromatin fragments in senescent cells. The activation of cGAS, in turn, triggers the production of SASP factors via stimulator of interferon genes (STING), thereby promoting paracrine senescence. We demonstrate that diverse stimuli of cellular senescence engage the cGAS–STING pathway in vitro and we show cGAS-dependent regulation of senescence following irradiation and oncogene activation in vivo. Our findings provide insights into the mechanisms underlying cellular senescence by establishing the cGAS–STING pathway as a crucial regulator of senescence and the SASP.

    更新日期:2017-09-07
  • Principles of refereeing
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-31

    Peer review is a key element of scientific publishing. Here we discuss what constitutes the ideal referee report.

    更新日期:2017-08-31
  • Enhancing brown fat with NFIA
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-31
    Suzanne N. Shapira, Patrick Seale

    Brown adipose tissue is a key metabolic organ that oxidizes fatty acids and glucose to generate heat. Through epigenomic analyses of multiple adipose depots, the transcription factor nuclear factor I-A (NFIA) is now shown to drive the brown fat genetic program through binding to lineage-specific cis-regulatory elements.

    更新日期:2017-08-31
  • A fruitful liaison of ZSCAN10 and ROS on the road to rejuvenation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-31
    Clea Bárcena, Carlos López-Otín

    Induced pluripotent stem cells derived from aged donors (A-iPSCs) usually show genomic instability that affects their utility and raises concerns about their safety. Now, a study highlights the importance of ZSCAN10-dependent recovery of glutathione–ROS homeostasis in counteracting the genomic defects in A-iPSCs.

    更新日期:2017-08-31
  • Lab-grown mini-brains upgraded
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-31
    Lin Yang, Huck-Hui Ng

    Three-dimensional brain organoid models have come into the spotlight as in vitro tools to recapitulate complex features of the brain. Four recent papers now leverage current technologies to generate new flavours of brain organoids and address aspects of brain biology which, to date, have been challenging to explore.

    更新日期:2017-08-31
  • DNA sensing in senescence
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-31
    Marina Ruiz de Galarreta, Amaia Lujambio

    Cellular senescence, a cell-autonomous growth arrest program, also executes pleiotropic non-cell-autonomous activities through the senescence-associated secretory phenotype (SASP). The innate cGAS–STING DNA-sensing pathway is now shown to regulate senescence by recognizing cytosolic DNA and inducing SASP factors, uncovering an unexpected link between these two previously unrelated pathways.

    更新日期:2017-08-31
  • Lactate dehydrogenase activity drives hair follicle stem cell activation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-14
    Aimee Flores, John Schell, Abigail S. Krall, David Jelinek, Matilde Miranda, Melina Grigorian, Daniel Braas, Andrew C. White, Jessica L. Zhou, Nicholas A. Graham, Thomas Graeber, Pankaj Seth, Denis Evseenko, Hilary A. Coller, Jared Rutter, Heather R. Christofk, William E. Lowry

    Although normally dormant, hair follicle stem cells (HFSCs) quickly become activated to divide during a new hair cycle. The quiescence of HFSCs is known to be regulated by a number of intrinsic and extrinsic mechanisms. Here we provide several lines of evidence to demonstrate that HFSCs utilize glycolytic metabolism and produce significantly more lactate than other cells in the epidermis. Furthermore, lactate generation appears to be critical for the activation of HFSCs as deletion of lactate dehydrogenase (Ldha) prevented their activation. Conversely, genetically promoting lactate production in HFSCs through mitochondrial pyruvate carrier 1 (Mpc1) deletion accelerated their activation and the hair cycle. Finally, we identify small molecules that increase lactate production by stimulating Myc levels or inhibiting Mpc1 carrier activity and can topically induce the hair cycle. These data suggest that HFSCs maintain a metabolic state that allows them to remain dormant and yet quickly respond to appropriate proliferative stimuli.

    更新日期:2017-08-31
  • A caspase-independent way to kill cancer cells
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-31
    Brent E. Fitzwalter, Andrew Thorburn

    Cancer treatments often focus on killing tumour cells through apoptosis, which is thought to typically require mitochondrial outer membrane permeabilization (MOMP) and subsequent caspase activation. A study now shows that MOMP can trigger TNF-dependent, but caspase-independent cell death, suggesting a different approach to improve cancer therapy.

    更新日期:2017-08-31
  • Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-14
    John C. Schell, Dona R. Wisidagama, Claire Bensard, Helong Zhao, Peng Wei, Jason Tanner, Aimee Flores, Jeffrey Mohlman, Lise K. Sorensen, Christian S. Earl, Kristofor A. Olson, Ren Miao, T. Cameron Waller, Don Delker, Priyanka Kanth, Lei Jiang, Ralph J. DeBerardinis, Mary P. Bronner, Dean Y. Li, James E. Cox, Heather R. Christofk, William E. Lowry, Carl S. Thummel, Jared Rutter

    Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells.

    更新日期:2017-08-31
  • ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-28
    Maria Skamagki, Cristina Correia, Percy Yeung, Timour Baslan, Samuel Beck, Cheng Zhang, Christian A. Ross, Lam Dang, Zhong Liu, Simona Giunta, Tzu-Pei Chang, Joye Wang, Aparna Ananthanarayanan, Martina Bohndorf, Benedikt Bosbach, James Adjaye, Hironori Funabiki, Jonghwan Kim, Scott Lowe, James J. Collins, Chi-Wei Lu, Hu Li, Rui Zhao, Kitai Kim

    Induced pluripotent stem cells (iPSCs), which are used to produce transplantable tissues, may particularly benefit older patients, who are more likely to suffer from degenerative diseases. However, iPSCs generated from aged donors (A-iPSCs) exhibit higher genomic instability, defects in apoptosis and a blunted DNA damage response compared with iPSCs generated from younger donors. We demonstrated that A-iPSCs exhibit excessive glutathione-mediated reactive oxygen species (ROS) scavenging activity, which blocks the DNA damage response and apoptosis and permits survival of cells with genomic instability. We found that the pluripotency factor ZSCAN10 is poorly expressed in A-iPSCs and addition of ZSCAN10 to the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) during A-iPSC reprogramming normalizes ROS–glutathione homeostasis and the DNA damage response, and recovers genomic stability. Correcting the genomic instability of A-iPSCs will ultimately enhance our ability to produce histocompatible functional tissues from older patients’ own cells that are safe for transplantation.

    更新日期:2017-08-31
  • An apical MRCK-driven morphogenetic pathway controls epithelial polarity
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-21
    Ceniz Zihni, Evi Vlassaks, Stephen Terry, Jeremy Carlton, Thomas King Chor Leung, Michael Olson, Franck Pichaud, Maria Susana Balda, Karl Matter

    Polarized epithelia develop distinct cell surface domains, with the apical membrane acquiring characteristic morphological features such as microvilli. Cell polarization is driven by polarity determinants including the evolutionarily conserved partitioning-defective (PAR) proteins that are separated into distinct cortical domains. PAR protein segregation is thought to be a consequence of asymmetric actomyosin contractions. The mechanism of activation of apically polarized actomyosin contractility is unknown. Here we show that the Cdc42 effector MRCK activates myosin-II at the apical pole to segregate aPKC–Par6 from junctional Par3, defining the apical domain. Apically polarized MRCK-activated actomyosin contractility is reinforced by cooperation with aPKC–Par6 downregulating antagonistic RhoA-driven junctional actomyosin contractility, and drives polarization of cytosolic brush border determinants and apical morphogenesis. MRCK-activated polarized actomyosin contractility is required for apical differentiation and morphogenesis in vertebrate epithelia and Drosophila photoreceptors. Our results identify an apical origin of actomyosin-driven morphogenesis that couples cytoskeletal reorganization to PAR polarity signalling.

    更新日期:2017-08-31
  • Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-31
    Selene Glück, Baptiste Guey, Muhammet Fatih Gulen, Katharina Wolter, Tae-Won Kang, Niklas Arndt Schmacke, Anne Bridgeman, Jan Rehwinkel, Lars Zender, Andrea Ablasser

    Cellular senescence is triggered by various distinct stresses and characterized by a permanent cell cycle arrest. Senescent cells secrete a variety of inflammatory factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The mechanism(s) underlying the regulation of the SASP remains incompletely understood. Here we define a role for innate DNA sensing in the regulation of senescence and the SASP. We find that cyclic GMP-AMP synthase (cGAS) recognizes cytosolic chromatin fragments in senescent cells. The activation of cGAS, in turn, triggers the production of SASP factors via stimulator of interferon genes (STING), thereby promoting paracrine senescence. We demonstrate that diverse stimuli of cellular senescence engage the cGAS–STING pathway in vitro and we show cGAS-dependent regulation of senescence following irradiation and oncogene activation in vivo. Our findings provide insights into the mechanisms underlying cellular senescence by establishing the cGAS–STING pathway as a crucial regulator of senescence and the SASP.

    更新日期:2017-08-31
  • SMC complexes differentially compact mitotic chromosomes according to genomic context
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-21
    Stephanie Andrea Schalbetter, Anton Goloborodko, Geoffrey Fudenberg, Jon-Matthew Belton, Catrina Miles, Miao Yu, Job Dekker, Leonid Mirny, Jonathan Baxter

    Structural maintenance of chromosomes (SMC) protein complexes are key determinants of chromosome conformation. Using Hi-C and polymer modelling, we study how cohesin and condensin, two deeply conserved SMC complexes, organize chromosomes in the budding yeast Saccharomyces cerevisiae. The canonical role of cohesin is to co-align sister chromatids, while condensin generally compacts mitotic chromosomes. We find strikingly different roles for the two complexes in budding yeast mitosis. First, cohesin is responsible for compacting mitotic chromosome arms, independently of sister chromatid cohesion. Polymer simulations demonstrate that this role can be fully accounted for through cis-looping of chromatin. Second, condensin is generally dispensable for compaction along chromosome arms. Instead, it plays a targeted role compacting the rDNA proximal regions and promoting resolution of peri-centromeric regions. Our results argue that the conserved mechanism of SMC complexes is to form chromatin loops and that distinct SMC-dependent looping activities are selectively deployed to appropriately compact chromosomes.

    更新日期:2017-08-31
  • NFIA co-localizes with PPARγ and transcriptionally controls the brown fat gene program
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-14
    Yuta Hiraike, Hironori Waki, Jing Yu, Masahiro Nakamura, Kana Miyake, Gaku Nagano, Ryo Nakaki, Ken Suzuki, Hirofumi Kobayashi, Shogo Yamamoto, Wei Sun, Tomohisa Aoyama, Yusuke Hirota, Haruya Ohno, Kenji Oki, Masayasu Yoneda, Andrew P. White, Yu-Hua Tseng, Aaron M. Cypess, Therese J. Larsen, Naja Z. Jespersen, Camilla Scheele, Shuichi Tsutsumi, Hiroyuki Aburatani, Toshimasa Yamauchi, Takashi Kadowaki

    Brown fat dissipates energy as heat and protects against obesity. Here, we identified nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of brown-fat-specific open chromatin regions. NFIA and the master transcriptional regulator of adipogenesis, PPARγ, co-localize at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARγ, leading to increased chromatin accessibility and active transcription. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA-knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. Finally, expression of NFIA and the brown-fat-specific genes is positively correlated in human brown fat. These results indicate that NFIA activates the cell-type-specific enhancers and facilitates the binding of PPARγ to control the brown fat gene program.

    更新日期:2017-08-31
  • Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-21
    Sarah J. Horton, George Giotopoulos, Haiyang Yun, Shabana Vohra, Olivia Sheppard, Rachael Bashford-Rogers, Mamunur Rashid, Alexandra Clipson, Wai-In Chan, Daniel Sasca, Loukia Yiangou, Hikari Osaki, Faisal Basheer, Paolo Gallipoli, Natalie Burrows, Ayşegül Erdem, Anastasiya Sybirna, Sarah Foerster, Wanfeng Zhao, Tonci Sustic, Anna Petrunkina Harrison, Elisa Laurenti, Jessica Okosun, Daniel Hodson, Penny Wright, Ken G. Smith, Patrick Maxwell, Jude Fitzgibbon, Ming Q. Du, David J. Adams, Brian J. P. Huntly

    Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies.

    更新日期:2017-08-31
  • A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-21
    Simon Grelet, Laura A. Link, Breege Howley, Clémence Obellianne, Viswanathan Palanisamy, Vamsi K. Gangaraju, J. Alan Diehl, Philip H. Howe

    The contribution of lncRNAs to tumour progression and the regulatory mechanisms driving their expression are areas of intense investigation. Here, we characterize the binding of heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) to a nucleic acid structural element located in exon 12 of PNUTS (also known as PPP1R10) pre-RNA that regulates its alternative splicing. HnRNP E1 release from this structural element, following its silencing, nucleocytoplasmic translocation or in response to TGFβ, allows alternative splicing and generates a non-coding isoform of PNUTS. Functionally the lncRNA-PNUTS serves as a competitive sponge for miR-205 during epithelial–mesenchymal transition (EMT). In mesenchymal breast tumour cells and in breast tumour samples, the expression of lncRNA-PNUTS is elevated and correlates with levels of ZEB mRNAs. Thus, PNUTS is a bifunctional RNA encoding both PNUTS mRNA and lncRNA-PNUTS, each eliciting distinct biological functions. While PNUTS mRNA is ubiquitously expressed, lncRNA-PNUTS appears to be tightly regulated dependent on the status of hnRNP E1 and tumour context.

    更新日期:2017-08-31
  • Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-08-28
    Evangelos Giampazolias, Barbara Zunino, Sandeep Dhayade, Florian Bock, Catherine Cloix, Kai Cao, Alba Roca, Jonathan Lopez, Gabriel Ichim, Emma Proïcs, Camila Rubio-Patiño, Loic Fort, Nader Yatim, Emma Woodham, Susana Orozco, Lucia Taraborrelli, Nieves Peltzer, Daniele Lecis, Laura Machesky, Henning Walczak, Matthew L. Albert, Simon Milling, Andrew Oberst, Jean-Ehrland Ricci, Kevin M. Ryan, Karen Blyth, Stephen W. G. Tait

    Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies.

    更新日期:2017-08-31
  • Journal metrics: what's in a number?
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-28

    Metrics of research assessment should be applied with judgment and clarity to avoid undermining scientific efforts.

    更新日期:2017-07-30
  • Organelle biogenesis in the endoplasmic reticulum
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-17
    Amit S. Joshi, Hong Zhang, William A. Prinz

    Understanding organelle biogenesis is a central focus of cell biology. Whereas some are generated from existing organelles, others can be generated de novo. Most de novo organelle biogenesis occurs in the endoplasmic reticulum (ER). Here, we review the role of the ER in the generation of peroxisomes, lipid droplets, and omegasomes, which are platforms for autophagosome production, and discuss how ER subdomains with specific protein and lipid composition form and promote organelle biogenesis.

    更新日期:2017-07-30
  • CTCF fences make good neighbours
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-28
    Ivan Krivega, Ann Dean

    CCCTC-binding factor (CTCF) sites are enriched at the boundaries of topologically associated domains (TADs), but their function within TADs is unclear. Removal of sub-TAD CTCF sites adjacent to the α-globin enhancers is now shown to result in inappropriate activation of neighbouring genes. Intra-TAD enhancer insulation might be broadly important for tissue specificity of enhancers.

    更新日期:2017-07-30
  • Origin and regulation of a lung repair kit
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-28
    Jichao Chen

    The lung undergoes a striking repair process in response to severe injuries such as influenza infection. A study now demonstrates that associated stem/progenitor cells are heterogeneous in nature and comprise subpopulations dominated by hypoxia/Notch or Wnt signalling. Modulation of this heterogeneity in favour of functional repair may have therapeutic value.

    更新日期:2017-07-30
  • The skinny on obesity and cancer
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-28
    Jaclyn Sceneay, Sandra S. McAllister

    Obesity now rivals smoking as one of the leading preventable causes of cancer. Obesity-associated neutrophilia is now shown to enhance breast cancer metastasis and to be reversible through dietary modification and weight loss.

    更新日期:2017-07-30
  • A key HDAC6 dependency of ARID1A-mutated ovarian cancer
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-28
    Lucia Altucci

    Mutations in AT rich interactive domain 1A (ARID1A) are common in ovarian cancers. A study now shows that HDAC6 activity is required for survival of ovarian cancer cells bearing ARID1A mutations. HDAC6 inhibition selectively promotes apoptosis of ARID1A-inactivated cells, supporting the use of HDAC6 inhibition in the treatment of clear cell ovarian cancer.

    更新日期:2017-07-30
  • Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-17
    Bo O. Zhou, Hua Yu, Rui Yue, Zhiyu Zhao, Jonathan J. Rios, Olaia Naveiras, Sean J. Morrison

    Endothelial cells and leptin receptor+ (LepR+) stromal cells are critical sources of haematopoietic stem cell (HSC) niche factors, including stem cell factor (SCF), in bone marrow. After irradiation or chemotherapy, these cells are depleted while adipocytes become abundant. We discovered that bone marrow adipocytes synthesize SCF. They arise from Adipoq-Cre/ER+ progenitors, which represent ~5% of LepR+ cells, and proliferate after irradiation. Scf deletion using Adipoq-Cre/ER inhibited haematopoietic regeneration after irradiation or 5-fluorouracil treatment, depleting HSCs and reducing mouse survival. Scf from LepR+ cells, but not endothelial, haematopoietic or osteoblastic cells, also promoted regeneration. In non-irradiated mice, Scf deletion using Adipoq-Cre/ER did not affect HSC frequency in long bones, which have few adipocytes, but depleted HSCs in tail vertebrae, which have abundant adipocytes. A-ZIP/F1 ‘fatless’ mice exhibited delayed haematopoietic regeneration in long bones but not in tail vertebrae, where adipocytes inhibited vascularization. Adipocytes are a niche component that promotes haematopoietic regeneration.

    更新日期:2017-07-30
  • Local lung hypoxia determines epithelial fate decisions during alveolar regeneration
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-24
    Ying Xi, Thomas Kim, Alexis N. Brumwell, Ian H. Driver, Ying Wei, Victor Tan, Julia R. Jackson, Jianming Xu, Dong-Kee Lee, Jeffrey E. Gotts, Michael A. Matthay, John M. Shannon, Harold A. Chapman, Andrew E. Vaughan

    After influenza infection, lineage-negative epithelial progenitors (LNEPs) exhibit a binary response to reconstitute epithelial barriers: activating a Notch-dependent ΔNp63/cytokeratin 5 (Krt5) remodelling program or differentiating into alveolar type II cells (AEC2s). Here we show that local lung hypoxia, through hypoxia-inducible factor (HIF1α), drives Notch signalling and Krt5pos basal-like cell expansion. Single-cell transcriptional profiling of human AEC2s from fibrotic lungs revealed a hypoxic subpopulation with activated Notch, suppressed surfactant protein C (SPC), and transdifferentiation toward a Krt5pos basal-like state. Activated murine Krt5pos LNEPs and diseased human AEC2s upregulate strikingly similar core pathways underlying migration and squamous metaplasia. While robust, HIF1α-driven metaplasia is ultimately inferior to AEC2 reconstitution in restoring normal lung function. HIF1α deletion or enhanced Wnt/β-catenin activity in Sox2pos LNEPs blocks Notch and Krt5 activation, instead promoting rapid AEC2 differentiation and migration and improving the quality of alveolar repair.

    更新日期:2017-07-30
  • Dll4 and Notch signalling couples sprouting angiogenesis and artery formation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-17
    Mara E. Pitulescu, Inga Schmidt, Benedetto Daniele Giaimo, Tobiah Antoine, Frank Berkenfeld, Francesca Ferrante, Hongryeol Park, Manuel Ehling, Daniel Biljes, Susana F. Rocha, Urs H. Langen, Martin Stehling, Takashi Nagasawa, Napoleone Ferrara, Tilman Borggrefe, Ralf H. Adams

    Endothelial sprouting and proliferation are tightly coordinated processes mediating the formation of new blood vessels during physiological and pathological angiogenesis. Endothelial tip cells lead sprouts and are thought to suppress tip-like behaviour in adjacent stalk endothelial cells by activating Notch. Here, we show with genetic experiments in postnatal mice that the level of active Notch signalling is more important than the direct Dll4-mediated cell–cell communication between endothelial cells. We identify endothelial expression of VEGF-A and of the chemokine receptor CXCR4 as key processes controlling Notch-dependent vessel growth. Surprisingly, genetic experiments targeting endothelial tip cells in vivo reveal that they retain their function without Dll4 and are also not replaced by adjacent, Dll4-positive cells. Instead, activation of Notch directs tip-derived endothelial cells into developing arteries and thereby establishes that Dll4–Notch signalling couples sprouting angiogenesis and artery formation.

    更新日期:2017-07-30
  • Endothelial Notch signalling limits angiogenesis via control of artery formation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-17
    Sana S. Hasan, Roman Tsaryk, Martin Lange, Laura Wisniewski, John C. Moore, Nathan D. Lawson, Karolina Wojciechowska, Hans Schnittler, Arndt F. Siekmann

    Angiogenic sprouting needs to be tightly controlled. It has been suggested that the Notch ligand dll4 expressed in leading tip cells restricts angiogenesis by activating Notch signalling in trailing stalk cells. Here, we show using live imaging in zebrafish that activation of Notch signalling is rather required in tip cells. Notch activation initially triggers expression of the chemokine receptor cxcr4a. This allows for proper tip cell migration and connection to the pre-existing arterial circulation, ultimately establishing functional arterial–venous blood flow patterns. Subsequently, Notch signalling reduces cxcr4a expression, thereby preventing excessive blood vessel growth. Finally, we find that Notch signalling is dispensable for limiting blood vessel growth during venous plexus formation that does not generate arteries. Together, these findings link the role of Notch signalling in limiting angiogenesis to its role during artery formation and provide a framework for our understanding of the mechanisms underlying blood vessel network expansion and maturation.

    更新日期:2017-07-30
  • Budding yeast Wee1 distinguishes spindle pole bodies to guide their pattern of age-dependent segregation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-17
    Jette Lengefeld, Manuel Hotz, Meaghen Rollins, Kristin Baetz, Yves Barral

    Many asymmetrically dividing cells unequally partition cellular structures according to age. Yet, it is unclear how cells differentiate pre-existing from newly synthesized material. Yeast cells segregate the spindle pole body (SPB, centrosome equivalent) inherited from the previous mitosis to the bud, while keeping the new one in the mother cell. Here, we show that the SPB inheritance network (SPIN), comprising the kinases Swe1 (also known as Wee1) and Kin3 (also known as Nek2) and the acetyltransferase NuA4 (also known as Tip60), distinguishes pre-existing from new SPBs. Swe1 phosphorylated Nud1 (orthologous to Centriolin) on young SPBs as they turned into pre-existing ones. The subsequent inactivation of Swe1 protected newly assembling SPBs from being marked. Kin3 and NuA4 maintained age marks on SPBs through following divisions. Downstream of SPIN, the Hippo regulator Bfa1–Bub2 bound the marked SPB, directed the spindle-positioning protein Kar9 towards it and drove its partition to the bud. Thus, coordination of SPIN activity and SPB assembly encodes age onto SPBs to enable their age-dependent segregation.

    更新日期:2017-07-30
  • Tissue-specific CTCF–cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-24
    Lars L. P. Hanssen, Mira T. Kassouf, A. Marieke Oudelaar, Daniel Biggs, Chris Preece, Damien J. Downes, Matthew Gosden, Jacqueline A. Sharpe, Jacqueline A. Sloane-Stanley, Jim R. Hughes, Benjamin Davies, Douglas R. Higgs

    The genome is organized via CTCF–cohesin-binding sites, which partition chromosomes into 1–5 megabase (Mb) topologically associated domains (TADs), and further into smaller sub-domains (sub-TADs). Here we examined in vivo an ~80 kb sub-TAD, containing the mouse α-globin gene cluster, lying within a ~1 Mb TAD. We find that the sub-TAD is flanked by predominantly convergent CTCF–cohesin sites that are ubiquitously bound by CTCF but only interact during erythropoiesis, defining a self-interacting erythroid compartment. Whereas the α-globin regulatory elements normally act solely on promoters downstream of the enhancers, removal of a conserved upstream CTCF–cohesin boundary extends the sub-TAD to adjacent upstream CTCF–cohesin-binding sites. The α-globin enhancers now interact with the flanking chromatin, upregulating expression of genes within this extended sub-TAD. Rather than acting solely as a barrier to chromatin modification, CTCF–cohesin boundaries in this sub-TAD delimit the region of chromatin to which enhancers have access and within which they interact with receptive promoters.

    更新日期:2017-07-30
  • ARID1A-mutated ovarian cancers depend on HDAC6 activity
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-24
    Benjamin G. Bitler, Shuai Wu, Pyoung Hwa Park, Yang Hai, Katherine M. Aird, Yemin Wang, Yali Zhai, Andrew V. Kossenkov, Ana Vara-Ailor, Frank J. Rauscher III, Weiping Zou, David W. Speicher, David G. Huntsman, Jose R. Conejo-Garcia, Kathleen R. Cho, David W. Christianson, Rugang Zhang

    ARID1A, encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be explored. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small-molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated tumours. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumours. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylates Lys120 of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates the apoptosis-promoting function of p53 by upregulating HDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeutic strategy for ARID1A-mutated cancers.

    更新日期:2017-07-30
  • Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-24
    Daniela F. Quail, Oakley C. Olson, Priya Bhardwaj, Logan A. Walsh, Leila Akkari, Marsha L. Quick, I-Chun Chen, Nils Wendel, Nir Ben-Chetrit, Jeanne Walker, Peter R. Holt, Andrew J. Dannenberg, Johanna A. Joyce

    Obesity is associated with chronic, low-grade inflammation, which can disrupt homeostasis within tissue microenvironments. Given the correlation between obesity and relative risk of death from cancer, we investigated whether obesity-associated inflammation promotes metastatic progression. We demonstrate that obesity causes lung neutrophilia in otherwise normal mice, which is further exacerbated by the presence of a primary tumour. The increase in lung neutrophils translates to increased breast cancer metastasis to this site, in a GM-CSF- and IL5-dependent manner. Importantly, weight loss is sufficient to reverse this effect, and reduce serum levels of GM-CSF and IL5 in both mouse models and humans. Our data indicate that special consideration of the obese patient population is critical for effective management of cancer progression.

    更新日期:2017-07-30
  • Cortical forces and CDC-42 control clustering of PAR proteins for Caenorhabditis elegans embryonic polarization
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-24
    Shyi-Chyi Wang, Tricia Yu Feng Low, Yukako Nishimura, Laurent Gole, Weimiao Yu, Fumio Motegi

    Studying polarity establishment in C. elegans zygotes, Wang et al. find, by imaging GFP-tagged proteins, that clusters of the PAR-3 polarity protein assemble in response to membrane tension created by actomyosin contractility.

    更新日期:2017-07-30
  • Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-28
    Kimberly C. Lin, Toshiro Moroishi, Zhipeng Meng, Han-Sol Jeong, Steven W. Plouffe, Yoshitaka Sekido, Jiahuai Han, Hyun Woo Park, Kun-Liang Guan

    Lin et al. find that stress-induced p38 MAPK activation leads to cytoplasmic relocation of the Hippo pathway nuclear transcription factor TEAD. TEAD relocation causes inhibition of YAP activity and suppresses YAP-driven cancer cell growth.

    更新日期:2017-07-30
  • ARID1A-mutated ovarian cancers depend on HDAC6 activity
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-24
    Benjamin G. Bitler, Shuai Wu, Pyoung Hwa Park, Yang Hai, Katherine M. Aird, Yemin Wang, Yali Zhai, Andrew V. Kossenkov, Ana Vara-Ailor, Frank J. Rauscher III, Weiping Zou, David W. Speicher, David G. Huntsman, Jose R. Conejo-Garcia, Kathleen R. Cho, David W. Christianson, Rugang Zhang

    ARID1A, encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be explored. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small-molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated tumours. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumours. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylates Lys120 of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates the apoptosis-promoting function of p53 by upregulating HDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeutic strategy for ARID1A-mutated cancers.

    更新日期:2017-07-25
  • Tissue-specific CTCF–cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-24
    Lars L. P. Hanssen, Mira T. Kassouf, A. Marieke Oudelaar, Daniel Biggs, Chris Preece, Damien J. Downes, Matthew Gosden, Jacqueline A. Sharpe, Jacqueline A. Sloane-Stanley, Jim R. Hughes, Benjamin Davies, Douglas R. Higgs

    The genome is organized via CTCF–cohesin-binding sites, which partition chromosomes into 1–5 megabase (Mb) topologically associated domains (TADs), and further into smaller sub-domains (sub-TADs). Here we examined in vivo an ~80 kb sub-TAD, containing the mouse α-globin gene cluster, lying within a ~1 Mb TAD. We find that the sub-TAD is flanked by predominantly convergent CTCF–cohesin sites that are ubiquitously bound by CTCF but only interact during erythropoiesis, defining a self-interacting erythroid compartment. Whereas the α-globin regulatory elements normally act solely on promoters downstream of the enhancers, removal of a conserved upstream CTCF–cohesin boundary extends the sub-TAD to adjacent upstream CTCF–cohesin-binding sites. The α-globin enhancers now interact with the flanking chromatin, upregulating expression of genes within this extended sub-TAD. Rather than acting solely as a barrier to chromatin modification, CTCF–cohesin boundaries in this sub-TAD delimit the region of chromatin to which enhancers have access and within which they interact with receptive promoters.

    更新日期:2017-07-25
  • Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-24
    Daniela F. Quail, Oakley C. Olson, Priya Bhardwaj, Logan A. Walsh, Leila Akkari, Marsha L. Quick, I-Chun Chen, Nils Wendel, Nir Ben-Chetrit, Jeanne Walker, Peter R. Holt, Andrew J. Dannenberg, Johanna A. Joyce

    Obesity is associated with chronic, low-grade inflammation, which can disrupt homeostasis within tissue microenvironments. Given the correlation between obesity and relative risk of death from cancer, we investigated whether obesity-associated inflammation promotes metastatic progression. We demonstrate that obesity causes lung neutrophilia in otherwise normal mice, which is further exacerbated by the presence of a primary tumour. The increase in lung neutrophils translates to increased breast cancer metastasis to this site, in a GM-CSF- and IL5-dependent manner. Importantly, weight loss is sufficient to reverse this effect, and reduce serum levels of GM-CSF and IL5 in both mouse models and humans. Our data indicate that special consideration of the obese patient population is critical for effective management of cancer progression.

    更新日期:2017-07-25
  • Local lung hypoxia determines epithelial fate decisions during alveolar regeneration
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-24
    Ying Xi, Thomas Kim, Alexis N. Brumwell, Ian H. Driver, Ying Wei, Victor Tan, Julia R. Jackson, Jianming Xu, Dong-Kee Lee, Jeffrey E. Gotts, Michael A. Matthay, John M. Shannon, Harold A. Chapman, Andrew E. Vaughan

    After influenza infection, lineage-negative epithelial progenitors (LNEPs) exhibit a binary response to reconstitute epithelial barriers: activating a Notch-dependent ΔNp63/cytokeratin 5 (Krt5) remodelling program or differentiating into alveolar type II cells (AEC2s). Here we show that local lung hypoxia, through hypoxia-inducible factor (HIF1α), drives Notch signalling and Krt5pos basal-like cell expansion. Single-cell transcriptional profiling of human AEC2s from fibrotic lungs revealed a hypoxic subpopulation with activated Notch, suppressed surfactant protein C (SPC), and transdifferentiation toward a Krt5pos basal-like state. Activated murine Krt5pos LNEPs and diseased human AEC2s upregulate strikingly similar core pathways underlying migration and squamous metaplasia. While robust, HIF1α-driven metaplasia is ultimately inferior to AEC2 reconstitution in restoring normal lung function. HIF1α deletion or enhanced Wnt/β-catenin activity in Sox2pos LNEPs blocks Notch and Krt5 activation, instead promoting rapid AEC2 differentiation and migration and improving the quality of alveolar repair.

    更新日期:2017-07-25
  • Cortical forces and CDC-42 control clustering of PAR proteins for Caenorhabditis elegans embryonic polarization
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-24
    Shyi-Chyi Wang, Tricia Yu Feng Low, Yukako Nishimura, Laurent Gole, Weimiao Yu, Fumio Motegi

    Studying polarity establishment in C. elegans zygotes, Wang et al. find, by imaging GFP-tagged proteins, that clusters of the PAR-3 polarity protein assemble in response to membrane tension created by actomyosin contractility.

    更新日期:2017-07-25
  • Organelle biogenesis in the endoplasmic reticulum
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-17

    In this Review, Prinz and co-authors discuss the role of the endoplasmic reticulum (ER) in the de novo generation of peroxisomes, lipid droplets and omegasomes, and how this requires subdomains with specific protein and lipid compositions.

    更新日期:2017-07-18
  • Endothelial Notch signalling limits angiogenesis via control of artery formation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-17

    Pitulescu et al. and Hasan et al. show that Dll4–Notch signalling in endothelial tip cells regulates angiogenesis through control of artery formation, linking sprouting angiogenesis and artery formation.

    更新日期:2017-07-18
  • Budding yeast Wee1 distinguishes spindle pole bodies to guide their pattern of age-dependent segregation
    Nat. Cell. Biol. (IF 20.06) Pub Date : 2017-07-17

    Lengefeld et al. reveal how yeast cells distinguish between newly synthesized and pre-existing spindle pole bodies to enable their asymmetric segregation, through a mechanism involving Swe1, Kin3 and NuA4.

    更新日期:2017-07-18
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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