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  • Chromatin accessibility dynamics during cell fate reprogramming
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-22
    Dongwei Li; Xiaodong Shu; Ping Zhu; Duanqing Pei

    Genome architecture and chromatin dynamics govern the fate and identify of a cell. Recent advances in mapping chromatin landscapes offer valuable tools for the acquisition of accurate information regarding chromatin dynamics. Here we discuss recent findings linking chromatin dynamics to cell fate control. Specifically, chromatin undergoes a binary off/on switch during iPSC reprogramming, closing and

  • Transient deSUMOylation of IRF2BP proteins controls early transcription in EGFR signaling
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-22
    Sina V Barysch; Nicolas Stankovic‐Valentin; Tim Miedema; Samir Karaca; Judith Doppel; Thiziri Nait Achour; Aarushi Vasudeva; Lucie Wolf; Carsten Sticht; Henning Urlaub; Frauke Melchior

    Molecular switches are essential modules in signaling networks and transcriptional reprogramming. Here, we describe a role for small ubiquitin‐related modifier SUMO as a molecular switch in epidermal growth factor receptor (EGFR) signaling. Using quantitative mass spectrometry, we compare the endogenous SUMO proteomes of HeLa cells before and after EGF stimulation. Thereby, we identify a small group

  • Phosphodiesterase 4A confers resistance to PGE2‐mediated suppression in CD25+/CD54+ NK cells
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-22
    Ziqing Chen; Ying Yang; Shi Y Neo; Hao Shi; Yi Chen; Arnika K Wagner; Karin Larsson; Le Tong; Per‐Johan Jakobsson; Evren Alici; Jing Wu; Yihai Cao; Kai Wang; Lisa L Liu; Yumeng Mao; Dhifaf Sarhan; Andreas Lundqvist

    Inadequate persistence of tumor‐infiltrating natural killer (NK) cells is associated with poor prognosis in cancer patients. The solid tumor microenvironment is characterized by the presence of immunosuppressive factors, including prostaglandin E2 (PGE2), that limit NK cell persistence. Here, we investigate if the modulation of the cytokine environment in lung cancer with IL‐2 or IL‐15 renders NK cells

  • Structural basis of transport and inhibition of the Plasmodium falciparum transporter PfFNT
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-20
    Meinan Lyu; Chih‐Chia Su; James W Kazura; Edward W Yu

    The intra‐erythrocyte stage of P. falciparum relies primarily on glycolysis to generate adenosine triphosphate (ATP) and the energy required to support growth and reproduction. Lactic acid, a metabolic byproduct of glycolysis, is potentially toxic as it lowers the pH inside the parasite. Plasmodium falciparum formate–nitrite transporter (PfFNT), a 34‐kDa transmembrane protein, has been identified as

  • Biogenic amine neurotransmitters promote eicosanoid production and protein homeostasis
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-20
    Kishore K Joshi; Tarmie L Matlack; Stephanie Pyonteck; Mehul Vora; Ralph Menzel; Christopher Rongo

    Metazoans use protein homeostasis (proteostasis) pathways to respond to adverse physiological conditions, changing environment, and aging. The nervous system regulates proteostasis in different tissues, but the mechanism is not understood. Here, we show that Caenorhabditis elegans employs biogenic amine neurotransmitters to regulate ubiquitin proteasome system (UPS) proteostasis in epithelia. Mutants

  • A multifaceted cellular damage repair and prevention pathway promotes high‐level tolerance to β‐lactam antibiotics
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-18
    Jung‐Ho Shin; Donghui Choe; Brett Ransegnola; Hye‐Rim Hong; Ikenna Onyekwere; Trevor Cross; Qiaojuan Shi; Byung‐Kwan Cho; Lars F Westblade; Ilana L Brito; Tobias Dörr

    Bactericidal antibiotics are powerful agents due to their ability to convert essential bacterial functions into lethal processes. However, many important bacterial pathogens are remarkably tolerant against bactericidal antibiotics due to inducible damage repair responses. The cell wall damage response two‐component system VxrAB of the gastrointestinal pathogen Vibrio cholerae promotes high‐level β‐lactam

  • MYC promotes cancer progression by modulating m6A modifications to suppress target gene translation
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-11
    Gongwei Wu; Caixia Suo; Ying Yang; Shengqi Shen; Linchong Sun; Shi‐Ting Li; Yingli Zhou; Dongdong Yang; Yan Wang; Yongping Cai; Nana Wang; Huafeng Zhang; Yun‐Gui Yang; Jie Cao; Ping Gao

    The MYC oncoprotein activates and represses gene expression in a transcription‐dependent or transcription‐independent manner. Modification of mRNA emerges as a key gene expression regulatory nexus. We sought to determine whether MYC alters mRNA modifications and report here that MYC promotes cancer progression by down‐regulating N6‐methyladenosine (m6A) preferentially in transcripts of a subset of

  • Bardet–Biedl Syndrome ciliopathy is linked to altered hematopoiesis and dysregulated self‐tolerance
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-11
    Oksana Tsyklauri; Veronika Niederlova; Elizabeth Forsythe; Avishek Prasai; Ales Drobek; Petr Kasparek; Kathryn Sparks; Zdenek Trachtulec; Jan Prochazka; Radislav Sedlacek; Philip Beales; Martina Huranova; Ondrej Stepanek

    Bardet–Biedl Syndrome (BBS) is a pleiotropic genetic disease caused by the dysfunction of primary cilia. The immune system of patients with ciliopathies has not been investigated. However, there are multiple indications that the impairment of the processes typically associated with cilia may have influence on the hematopoietic compartment and immunity. In this study, we analyze clinical data of BBS

  • Root endophyte induced plant thermotolerance by constitutive chromatin modification at heat stress memory gene loci
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-10
    Kirti Shekhawat; Maged M Saad; Arsheed Sheikh; Kiruthiga Mariappan; Henda Al‐Mahmoudi; Fatimah Abdulhakim; Abdul Aziz Eida; Rewaa Jalal; Khaled Masmoudi; Heribert Hirt

    Global warming has become a critical challenge to food security, causing severe yield losses of major crops worldwide. Conventional and transgenic breeding strategies to enhance plant thermotolerance are laborious and expensive. Therefore, the use of beneficial microbes could be an alternative approach. Here, we report that the root endophyte Enterobacter sp. SA187 induces thermotolerance in wheat

  • Gradual centriole maturation associates with the mitotic surveillance pathway in mouse development
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-07
    Cally Xiao; Marta Grzonka; Charlotte Meyer‐Gerards; Miriam Mack; Rebecca Figge; Hisham Bazzi

    Centrosomes, composed of two centrioles and pericentriolar material, organize mitotic spindles during cell division and template cilia during interphase. The first few divisions during mouse development occur without centrioles, which form around embryonic day (E) 3. However, disruption of centriole biogenesis in Sas‐4 null mice leads to embryonic arrest around E9. Centriole loss in Sas‐4−/− embryos

  • Epigenetic regulator Stuxnet modulates octopamine effect on sleep through a Stuxnet‐Polycomb‐Octβ2R cascade
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-07
    Zhangwu Zhao; Xianguo Zhao; Tao He; Xiaoyu Wu; Pengfei Lv; Alan J; Juan Du

    Sleep homeostasis is crucial for sleep regulation. The role of epigenetic regulation in sleep homeostasis is unestablished. Previous studies showed that octopamine is important for sleep homeostasis. However, the regulatory mechanism of octopamine reception in sleep is unknown. In this study, we identify an epigenetic regulatory cascade (Stuxnet‐Polycomb‐Octβ2R) that modulates the octopamine receptor

  • Histone methyltransferase DOT1L controls state‐specific identity during B cell differentiation
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-07
    Muhammad Assad Aslam; Mir Farshid Alemdehy; Eliza Mari Kwesi‐Maliepaard; Fitriari Izzatunnisa Muhaimin; Marieta Caganova; Iris N Pardieck; Teun van den Brand; Tibor van Welsem; Iris de Rink; Ji‐Ying Song; Elzo de Wit; Ramon Arens; Heinz Jacobs; Fred van Leeuwen

    Differentiation of naïve peripheral B cells into terminally differentiated plasma cells is characterized by epigenetic alterations, yet the epigenetic mechanisms that control B‐cell fate remain unclear. Here, we identified a role for the histone H3K79 methyltransferase DOT1L in controlling B‐cell differentiation. Mouse B cells lacking Dot1L failed to establish germinal centers (GC) and normal humoral

  • MDM2 regulates RB levels during genotoxic stress
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-13
    Jesus Hernandez‐Monge; Mayra Martínez‐Sánchez; Adriana Rousset‐Roman; Ixaura Medina‐Medina; Vanesa Olivares‐Illana

    The retinoblastoma tumour suppressor protein (RB) regulates a number of diverse cellular functions including differentiation, angiogenesis, chromatin remodelling, senescence and apoptosis. The best‐characterised function of RB is cell cycle regulation, and it has been considered a phosphoprotein regulated by cyclin‐dependent kinases. In its hypophosphorylated form, RB binds the transcription factor

  • MOAP‐1‐mediated dissociation of p62/SQSTM1 bodies releases Keap1 and suppresses Nrf2 signaling
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-04
    Chong Teik Tan; Hao‐Chun Chang; Qiling Zhou; Chundong Yu; Nai Yang Fu; Kanaga Sabapathy; Victor C Yu

    Nrf2 signaling is vital for protecting cells against oxidative stress. However, its hyperactivation is frequently found in liver cancer through excessive build‐up of p62/SQSTM1 bodies that sequester Keap1, an adaptor of the E3‐ubiquitin ligase complex for Nrf2. Here, we report that the Bax‐binding protein MOAP‐1 regulates p62‐Keap1‐Nrf2 signaling through disruption of p62 bodies. Upon induction of

  • Tnfaip2/exoc3‐driven lipid metabolism is essential for stem cell differentiation and organ homeostasis
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-10
    Sarmistha Deb; Daniel A Felix; Philipp Koch; Maharshi Krishna Deb; Karol Szafranski; Katrin Buder; Mara Sannai; Marco Groth; Joanna Kirkpatrick; Stefan Pietsch; André Gollowitzer; Alexander Groß; Philip Riemenschneider; Andreas Koeberle; Cristina González‐Estévez; Karl Lenhard Rudolph

    Lipid metabolism influences stem cell maintenance and differentiation but genetic factors that control these processes remain to be delineated. Here, we identify Tnfaip2 as an inhibitor of reprogramming of mouse fibroblasts into induced pluripotent stem cells. Tnfaip2 knockout impairs differentiation of embryonic stem cells (ESCs), and knockdown of the planarian para‐ortholog, Smed‐exoc3, abrogates

  • Non‐recombinogenic roles for Rad52 in translesion synthesis during DNA damage tolerance
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-02
    María I Cano‐Linares; Aurora Yáñez‐Vilches; Néstor García‐Rodríguez; Marta Barrientos‐Moreno; Román González‐Prieto; Pedro San‐Segundo; Helle D Ulrich; Félix Prado

    DNA damage tolerance relies on homologous recombination (HR) and translesion synthesis (TLS) mechanisms to fill in the ssDNA gaps generated during passing of the replication fork over DNA lesions in the template. Whereas TLS requires specialized polymerases able to incorporate a dNTP opposite the lesion and is error‐prone, HR uses the sister chromatid and is mostly error‐free. We report that the HR

  • Redox activation of ATM enhances GSNOR translation to sustain mitophagy and tolerance to oxidative stress
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-27
    Claudia Cirotti; Salvatore Rizza; Paola Giglio; Noemi Poerio; Maria Francesca Allega; Giuseppina Claps; Chiara Pecorari; Ji‐Hoon Lee; Barbara Benassi; Daniela Barilà; Caroline Robert; Jonathan S Stamler; Francesco Cecconi; Maurizio Fraziano; Tanya T Paull; Giuseppe Filomeni

    The denitrosylase S‐nitrosoglutathione reductase (GSNOR) has been suggested to sustain mitochondrial removal by autophagy (mitophagy), functionally linking S‐nitrosylation to cell senescence and aging. In this study, we provide evidence that GSNOR is induced at the translational level in response to hydrogen peroxide and mitochondrial ROS. The use of selective pharmacological inhibitors and siRNA demonstrates

  • The FUS gene is dual‐coding with both proteins contributing to FUS‐mediated toxicity
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-23
    Marie A Brunet; Jean‐Francois Jacques; Sonya Nassari; Giulia E Tyzack; Philip McGoldrick; Lorne Zinman; Steve Jean; Janice Robertson; Rickie Patani; Xavier Roucou

    Novel functional coding sequences (altORFs) are camouflaged within annotated ones (CDS) in a different reading frame. We show here that an altORF is nested in the FUS CDS, encoding a conserved 170 amino acid protein, altFUS. AltFUS is endogenously expressed in human tissues, notably in the motor cortex and motor neurons. Over‐expression of wild‐type FUS and/or amyotrophic lateral sclerosis‐linked FUS

  • Male castration increases adiposity via small intestinal microbial alterations
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-23
    Tae Woong Whon; Hyun Sik Kim; Na‐Ri Shin; Eun Sung Jung; Euon Jung Tak; Hojun Sung; Mi‐Ja Jung; Yun‐Seok Jeong; Dong‐Wook Hyun; Pil Soo Kim; Yu Kyung Jang; Choong Hwan Lee; Jin‐Woo Bae

    Castration of young males is widely used in the cattle industry to improve meat quality, but the mechanism linking hypogonadism and host metabolism is not clear. Here, we use metataxonomic and metabolomic approaches to evaluate the intestinal microbiota and host metabolism in male, castrated male (CtM), and female cattle. After pubescence, the CtM cattle harbor distinct ileal microbiota dominated by

  • BRLF1 suppresses RNA Pol III‐mediated RIG‐I inflammasome activation in the early EBV lytic lifecycle
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-23
    Xubing Long; Jing Yang; Xiaolin Zhang; Ziwei Yang; Yang Li; Fan Wang; Xiaojuan Li; Ersheng Kuang

    Latent infection with herpesviruses constitutively activates inflammasomes, while lytic replication suppresses their activation through distinct mechanisms. However, how Epstein–Barr virus (EBV) lytic replication inhibits the activation of inflammasomes remains unknown. Here, we reveal that the EBV immediate‐early protein BRLF1 inhibits inflammasome activation, and BRLF1 deficiency significantly increases

  • OMA1 reprograms metabolism under hypoxia to promote colorectal cancer development
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-13
    Zhida Wu; Meiling Zuo; Ling Zeng; Kaisa Cui; Bing Liu; Chaojun Yan; Li Chen; Jun Dong; Fugen Shangguan; Wanglai Hu; He He; Bin Lu; Zhiyin Song

    Many cancer cells maintain enhanced aerobic glycolysis due to irreversible defective mitochondrial oxidative phosphorylation (OXPHOS). This phenomenon, known as the Warburg effect, is recently challenged because most cancer cells maintain OXPHOS. However, how cancer cells coordinate glycolysis and OXPHOS remains largely unknown. Here, we demonstrate that OMA1, a stress‐activated mitochondrial protease

  • AMPK regulates cell shape of cardiomyocytes by modulating turnover of microtubules through CLIP‐170
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-29
    Shohei Yashirogi; Takemasa Nagao; Yuya Nishida; Yusuke Takahashi; Tasneem Qaqorh; Issei Yazawa; Toru Katayama; Hidetaka Kioka; Tsubasa S Matsui; Shigeyoshi Saito; Yuki Masumura; Osamu Tsukamoto; Hisakazu Kato; Hiromichi Ueda; Osamu Yamaguchi; Kenta Yashiro; Satoru Yamazaki; Seiji Takashima; Yasunori Shintani

    AMP‐activated protein kinase (AMPK) is a multifunctional kinase that regulates microtubule (MT) dynamic instability through CLIP‐170 phosphorylation; however, its physiological relevance in vivo remains to be elucidated. In this study, we identified an active form of AMPK localized at the intercalated disks in the heart, a specific cell–cell junction present between cardiomyocytes. A contractile inhibitor

  • Dynamic folding modulation generates FGF21 variant against diabetes
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-09
    Lei Zhu; Hongxin Zhao; Juanjuan Liu; Hao Cai; Bo Wu; Zhijun Liu; Shu Zhou; Qingsong Liu; Xiaokun Li; Bin Bao; Jian Liu; Han Dai; Junfeng Wang

    Fibroblast growth factor 21 (FGF21) is a regulator of glucose and lipid metabolism. It has been widely considered as a promising candidate for the treatment of type 2 diabetes mellitus (T2DM) and other related metabolic disorders. However, lack of structural and dynamic information has limited FGF21‐based drug development. Here, using nuclear magnetic resonance (NMR) spectroscopy, we determine the

  • A splicing factor switch controls hematopoietic lineage specification of pluripotent stem cells
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-15
    Yapu Li; Ding Wang; Hongtao Wang; Xin Huang; Yuqi Wen; BingRui Wang; Changlu Xu; Jie Gao; Jinhua Liu; Jingyuan Tong; Mengge Wang; Pei Su; Sirui Ren; Feng Ma; Hong‐Dong Li; Emery H Bresnick; Jiaxi Zhou; Lihong Shi

    Alternative splicing (AS) leads to transcriptome diversity in eukaryotic cells and is one of the key regulators driving cellular differentiation. Although AS is of crucial importance for normal hematopoiesis and hematopoietic malignancies, its role in early hematopoietic development is still largely unknown. Here, by using high‐throughput transcriptomic analyses, we show that pervasive and dynamic

  • Rab11‐FIP1 mediates epithelial‐mesenchymal transition and invasion in esophageal cancer
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-06
    Qiaosi Tang; Ashley Lento; Kensuke Suzuki; Gizem Efe; Tatiana Karakasheva; Apple Long; Véronique Giroux; Mirazul Islam; E Paul Wileyto; Andres J Klein‐Szanto; Hiroshi Nakagawa; Adam Bass; Anil K Rustgi

    Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer worldwide. The most commonly mutated gene in ESCC is TP53. Using a combinatorial genetic and carcinogenic approach, we generate a novel mouse model of ESCC expressing either mutant or null p53 and show that mutant p53 exhibits enhanced tumorigenic properties and displays a distinct genomic profile. Through RNA‐seq

  • Paternal age affects offspring via an epigenetic mechanism involving REST/NRSF
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-05
    Kaichi Yoshizaki; Ryuichi Kimura; Hisato Kobayashi; Shinya Oki; Takako Kikkawa; Lingling Mai; Kohei Koike; Kentaro Mochizuki; Hitoshi Inada; Yasuhisa Matsui; Tomohiro Kono; Noriko Osumi

    Advanced paternal age can have deleterious effects on various traits in the next generation. Here, we establish a paternal‐aging model in mice to understand the molecular mechanisms of transgenerational epigenetics. Whole‐genome target DNA methylome analyses of sperm from aged mice reveal more hypo‐methylated genomic regions enriched in REST/NRSF binding motifs. Gene set enrichment analyses also reveal

  • Retinoblastoma protein promotes uterine epithelial cell cycle arrest and necroptosis for embryo invasion
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-05
    Shun Akaeda; Yasushi Hirota; Yamato Fukui; Shizu Aikawa; Ryoko Shimizu‐Hirota; Tetsuaki Kaku; Mona Gebril; Tomoyuki Hirata; Takehiro Hiraoka; Mitsunori Matsuo; Hirofumi Haraguchi; Mayuko Saito‐Kanatani; Norihiko Takeda; Tomoyuki Fujii; Yutaka Osuga

    Retinoblastoma protein (RB) encoded by Rb1 is a prominent inducer of cell cycle arrest (CCA). The hormone progesterone (P4) promotes CCA in the uterine epithelium and previous studies indicated that P4 activates RB by reducing the phosphorylated, inactive form of RB. Here, we show that embryo implantation is impaired in uterine‐specific Rb1 knockout mice. We observe persistent cell proliferation of

  • Actin filament oxidation by MICAL1 suppresses protections from cofilin‐induced disassembly
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-04
    Hugo Wioland; Stéphane Frémont; Bérengère Guichard; Arnaud Echard; Antoine Jégou; Guillaume Romet‐Lemonne

    Proteins of the ADF/cofilin family play a central role in the disassembly of actin filaments, and their activity must be tightly regulated in cells. Recently, the oxidation of actin filaments by the enzyme MICAL1 was found to amplify the severing action of cofilin through unclear mechanisms. Using single filament experiments in vitro, we found that actin filament oxidation by MICAL1 increases, by several

  • The deubiquitinase OTUD1 enhances iron transport and potentiates host antitumor immunity
    EMBO Rep. (IF 7.497) Pub Date : 2021-01-04
    Jia Song; Tongtong Liu; Yue Yin; Wei Zhao; Zhiqiang Lin; Yuxin Yin; Dan Lu; Fuping You

    Although iron is required for cell proliferation, iron‐dependent programmed cell death serves as a critical barrier to tumor growth and metastasis. Emerging evidence suggests that iron‐mediated lipid oxidation also facilitates immune eradication of cancer. However, the regulatory mechanisms of iron metabolism in cancer remain unclear. Here we identify OTUD1 as the deubiquitinase of iron‐responsive

  • Histone acetyltransferase 1 is a succinyltransferase for histones and non‐histones and promotes tumorigenesis
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-29
    Guang Yang; Ying Yuan; Hongfeng Yuan; Jiapei Wang; Haolin Yun; Yu Geng; Man Zhao; Linhan Li; Yejing Weng; Zixian Liu; Jinyan Feng; Yanan Bu; Lei Liu; Bingnan Wang; Xiaodong Zhang

    Lysine succinylation (Ksucc) is an evolutionarily conserved and widespread post‐translational modification. Histone acetyltransferase 1 (HAT1) is a type B histone acetyltransferase, regulating the acetylation of both histone and non‐histone proteins. However, the role of HAT1 in succinylation modulation remains unclear. Here, we employ a quantitative proteomics approach to study succinylation in HepG2

  • Coordinated control of adiposity and growth by anti‐anabolic kinase ERK7
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-28
    Kiran Hasygar; Onur Deniz; Ying Liu; Josef Gullmets; Riikka Hynynen; Hanna Ruhanen; Krista Kokki; Reijo Käkelä; Ville Hietakangas

    Energy storage and growth are coordinated in response to nutrient status of animals. How nutrient‐regulated signaling pathways control these processes in vivo remains insufficiently understood. Here, we establish an atypical MAP kinase, ERK7, as an inhibitor of adiposity and growth in Drosophila. ERK7 mutant larvae display elevated triacylglycerol (TAG) stores and accelerated growth rate, while overexpressed

  • Modeling by disruption and a selected‐for partner for the nude locus
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-28
    Jian Li; Yun‐Kyoung Lee; Wenyu Fu; Anne M Whalen; Mario C Estable; Laurel A Raftery; Kristin White; Lorin Weiner; Janice L Brissette

    A long‐standing problem in biology is how to dissect traits for which no tractable model exists. Here, we screen for genes like the nude locus (Foxn1)—genes central to mammalian hair and thymus development—using animals that never evolved hair, thymi, or Foxn1. Fruit flies are morphologically disrupted by the FOXN1 transcription factor and rescued by weak reductions in fly gene function, revealing

  • FAM111A induces nuclear dysfunction in disease and viral restriction
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-28
    Minghua Nie; Martina Oravcová; Yasaman Jami‐Alahmadi; James A Wohlschlegel; Eros Lazzerini‐Denchi; Michael N Boddy

    Mutations in the nuclear trypsin‐like serine protease FAM111A cause Kenny–Caffey syndrome (KCS2) with hypoparathyroidism and skeletal dysplasia or perinatally lethal osteocraniostenosis (OCS). In addition, FAM111A was identified as a restriction factor for certain host range mutants of the SV40 polyomavirus and VACV orthopoxvirus. However, because FAM111A function is poorly characterized, its roles

  • USP22 controls necroptosis by regulating receptor‐interacting protein kinase 3 ubiquitination
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-28
    Jens Roedig; Lisa Kowald; Thomas Juretschke; Rebekka Karlowitz; Behnaz Ahangarian Abhari; Heiko Roedig; Simone Fulda; Petra Beli; Sjoerd JL van Wijk

    Dynamic control of ubiquitination by deubiquitinating enzymes is essential for almost all biological processes. Ubiquitin‐specific peptidase 22 (USP22) is part of the SAGA complex and catalyzes the removal of mono‐ubiquitination from histones H2A and H2B, thereby regulating gene transcription. However, novel roles for USP22 have emerged recently, such as tumor development and cell death. Apart from

  • Paladin is a phosphoinositide phosphatase regulating endosomal VEGFR2 signalling and angiogenesis
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-28
    Anja Nitzsche; Riikka Pietilä; Dominic T Love; Chiara Testini; Takeshi Ninchoji; Ross O Smith; Elisabet Ekvärn; Jimmy Larsson; Francis P Roche; Isabel Egaña; Suvi Jauhiainen; Philipp Berger; Lena Claesson‐Welsh; Mats Hellström

    Cell signalling governs cellular behaviour and is therefore subject to tight spatiotemporal regulation. Signalling output is modulated by specialized cell membranes and vesicles which contain unique combinations of lipids and proteins. The phosphatidylinositol 4,5‐bisphosphate (PI(4,5)P2), an important component of the plasma membrane as well as other subcellular membranes, is involved in multiple

  • Pseudomonas aeruginosa survives in epithelia by ExoS‐mediated inhibition of autophagy and mTOR
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-20
    Lang Rao; Indhira De La Rosa; Yi Xu; Youbao Sha; Abhisek Bhattacharya; Michael J Holtzman; Brian E Gilbert; N Tony Eissa

    One major factor that contributes to the virulence of Pseudomonas aeruginosa is its ability to reside and replicate unchallenged inside airway epithelial cells. The mechanism by which P. aeruginosa escapes destruction by intracellular host defense mechanisms, such as autophagy, is not known. Here, we show that the type III secretion system effector protein ExoS facilitates P. aeruginosa survival in

  • Cancer‐secreted miRNAs regulate amino‐acid‐induced mTORC1 signaling and fibroblast protein synthesis
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-20
    Miranda Y Fong; Wei Yan; Majid Ghassemian; Xiwei Wu; Xin Zhou; Minghui Cao; Li Jiang; Jessica Wang; Xuxiang Liu; Jin Zhang; Shizhen Emily Wang

    Metabolic reprogramming of non‐cancer cells residing in a tumor microenvironment, as a result of the adaptations to cancer‐derived metabolic and non‐metabolic factors, is an emerging aspect of cancer–host interaction. We show that in normal and cancer‐associated fibroblasts, breast cancer‐secreted extracellular vesicles suppress mTOR signaling upon amino acid stimulation to globally reduce mRNA translation

  • Supercomplex formation boosts respiration
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-03
    Fabian den Brave; Thomas Becker

    Mitochondrial respiratory chain complexes associate in supercomplexes, but the physiological role of these assemblies remains controversial. Recent studies in EMBO Reports reveal that supercomplexes promote metabolic fitness. Berndtsson et al (2020) demonstrate that supercomplex formation enhances electron transport by reducing the distance for diffusion of cytochrome c between cytochrome bc1 complex

  • Hepatocyte ploidy modulation in liver cancer
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-25
    Andrew W Duncan

    Polyploidy, a balanced amplification of the genome, is common in the liver. The function of hepatic polyploidy is not entirely clear, but growing evidence shows that polyploidy can protect the liver from tumor formation. In this issue of EMBO Reports, Sladky and colleagues identify the PIDDosome as a polyploidy sensor that regulates liver cancer (Sladky et al, 2020b).

  • IRE1‐mediated miRNA maturation in macrophage phosphoinositide signaling
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-03
    Tony Avril; Eric Chevet

    Endoplasmic reticulum (ER) stress signaling has long been associated with various pathological states in particular with the development of diseases with an underlying inflammation, such as diabetes, liver or cardiovascular dysfunctions, and cancer. ER stress signaling is mediated by three stress sensors. The most evolutionarily conserved one, the inositol‐requiring enzyme 1 alpha (IRE1), transduces

  • Antibiotic resistance and persistence—Implications for human health and treatment perspectives
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-08
    Markus Huemer; Srikanth Mairpady Shambat; Silvio D Brugger; Annelies S Zinkernagel

    Antimicrobial resistance (AMR) and persistence are associated with an elevated risk of treatment failure and relapsing infections. They are thus important drivers of increased morbidity and mortality rates resulting in growing healthcare costs. Antibiotic resistance is readily identifiable with standard microbiological assays, and the threat imposed by antibiotic resistance has been well recognized

  • Regulation and inhibition of the DNA sensor cGAS
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-05
    Jonny Hertzog; Jan Rehwinkel

    Cell‐autonomous sensing of nucleic acids is essential for host defence against invading pathogens by inducing antiviral and inflammatory cytokines. cGAS has emerged in recent years as a non‐redundant DNA sensor important for detection of many viruses and bacteria. Upon binding to DNA, cGAS synthesises the cyclic dinucleotide 2′3′‐cGAMP that binds to the adaptor protein STING and thereby triggers IRF3‐

  • Respiratory supercomplexes enhance electron transport by decreasing cytochrome c diffusion distance
    EMBO Rep. (IF 7.497) Pub Date : 2020-10-05
    Jens Berndtsson; Andreas Aufschnaiter; Sorbhi Rathore; Lorena Marin‐Buera; Hannah Dawitz; Jutta Diessl; Verena Kohler; Antoni Barrientos; Sabrina Büttner; Flavia Fontanesi; Martin Ott

    Respiratory chains are crucial for cellular energy conversion and consist of multi‐subunit complexes that can assemble into supercomplexes. These structures have been intensively characterized in various organisms, but their physiological roles remain unclear. Here, we elucidate their function by leveraging a high‐resolution structural model of yeast respiratory supercomplexes that allowed us to inhibit

  • Chemical targeting of NEET proteins reveals their function in mitochondrial morphodynamics
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-12
    Diana Molino; Irene Pila‐Castellanos; Henri‐Baptiste Marjault; Nivea Dias Amoedo; Katja Kopp; Leila Rochin; Ola Karmi; Yang‐Sung Sohn; Laetitia Lines; Ahmed Hamaï; Stéphane Joly; Pauline Radreau; Jacky Vonderscher; Patrice Codogno; Francesca Giordano; Peter Machin; Rodrigue Rossignol; Eric Meldrum; Damien Arnoult; Alessia Ruggieri; Rachel Nechushtai; Benoit de Chassey; Etienne Morel

    Several human pathologies including neurological, cardiac, infectious, cancerous, and metabolic diseases have been associated with altered mitochondria morphodynamics. Here, we identify a small organic molecule, which we named Mito‐C. Mito‐C is targeted to mitochondria and rapidly provokes mitochondrial network fragmentation. Biochemical analyses reveal that Mito‐C is a member of a new class of heterocyclic

  • Influenza A viruses limit NLRP3‐NEK7‐complex formation and pyroptosis in human macrophages
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-12
    Inês Boal‐Carvalho; Béryl Mazel‐Sanchez; Filo Silva; Laure Garnier; Soner Yildiz; Joao PPL Bonifacio; Chengyue Niu; Nathalia Williams; Patrice Francois; Nicolaus Schwerk; Jennifer Schöning; Julia Carlens; Dorothee Viemann; Stephanie Hugues; Mirco Schmolke

    Pyroptosis is a fulminant form of macrophage cell death, contributing to release of pro‐inflammatory cytokines. In humans, it depends on caspase 1/4‐activation of gasdermin D and is characterized by the release of cytoplasmic content. Pathogens apply strategies to avoid or antagonize this host response. We demonstrate here that a small accessory protein (PB1‐F2) of contemporary H5N1 and H3N2 influenza

  • SARS‐CoV‐2 evades immune detection in alveolar macrophages
    EMBO Rep. (IF 7.497) Pub Date : 2020-10-28
    Louise Dalskov; Michelle Møhlenberg; Jacob Thyrsted; Julia Blay‐Cadanet; Ebbe Toftgaard Poulsen; Birgitte Holst Folkersen; Søren Helbo Skaarup; David Olagnier; Line Reinert; Jan Johannes Enghild; Hans Jürgen Hoffmann; Christian Kanstrup Holm; Rune Hartmann

    Respiratory infections, like the current COVID‐19 pandemic, target epithelial cells in the respiratory tract. Alveolar macrophages (AMs) are tissue‐resident macrophages located within the lung. They play a key role in the early phases of an immune response to respiratory viruses. AMs are likely the first immune cells to encounter SARS‐CoV‐2 during an infection, and their reaction to the virus will

  • N‐glycosylation of PD‐1 promotes binding of camrelizumab
    EMBO Rep. (IF 7.497) Pub Date : 2020-10-15
    Kefang Liu; Shuguang Tan; Wanjun Jin; Jiawei Guan; Qingling Wang; Huan Sun; Jianxun Qi; Jinghua Yan; Yan Chai; Zhongfu Wang; Chuxia Deng; George F Gao

    PD‐1 is a highly glycosylated inhibitory receptor expressed mainly on T cells. Targeting of PD‐1 with monoclonal antibodies (MAbs) to block the interaction with its ligand PD‐L1 has been successful for the treatment of multiple tumors. However, polymorphisms at N‐glycosylation sites of PD‐1 exist in the human population that might affect antibody binding, and dysregulated glycosylation has been observed

  • Atg1 kinase regulates autophagosome‐vacuole fusion by controlling SNARE bundling
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-03
    Saskia Barz; Franziska Kriegenburg; Anna Henning; Anuradha Bhattacharya; Hector Mancilla; Pablo Sánchez‐Martín; Claudine Kraft

    Autophagy mediates the degradation of cytoplasmic material. Upon autophagy induction, autophagosomes form a sealed membrane around the cargo and fuse with the lytic compartment to release the cargo for degradation. In order to avoid premature fusion of immature autophagosomal membranes with the lytic compartment, this process needs to be tightly regulated. Several factors mediating autophagosome–vacuole

  • Single‐cell transcriptome analysis reveals thyrocyte diversity in the zebrafish thyroid gland
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-03
    Pierre Gillotay; Meghna Shankar; Benoit Haerlingen; Eski Sema Elif; Macarena Pozo‐Morales; Inés Garteizgogeascoa; Susanne Reinhardt; Annekathrin Kränkel; Juliane Bläsche; Andreas Petzold; Nikolay Ninov; Gokul Kesavan; Christian Lange; Michael Brand; Anne Lefort; Frédérick Libert; Vincent Detours; Sabine Costagliola; Singh Sumeet Pal

    The thyroid gland regulates growth and metabolism via production of thyroid hormone in follicles composed of thyrocytes. So far, thyrocytes have been assumed to be a homogenous population. To uncover heterogeneity in the thyrocyte population and molecularly characterize the non‐thyrocyte cells surrounding the follicle, we developed a single‐cell transcriptome atlas of the region containing the zebrafish

  • Inositol‐requiring enzyme‐1 regulates phosphoinositide signaling lipids and macrophage growth
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-02
    Syed Muhammad Hamid; Mevlut Citir; Erdem Murat Terzi; Ismail Cimen; Zehra Yildirim; Asli Ekin Dogan; Begum Kocaturk; Umut Inci Onat; Moshe Arditi; Christian Weber; Alexis Traynor‐Kaplan; Carsten Schultz; Ebru Erbay

    The ER‐bound kinase/endoribonuclease (RNase), inositol‐requiring enzyme‐1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1’s one known, specific RNA target, X box‐binding protein‐1 (XBP1) or the RNA substrates of IRE1‐dependent RNA degradation (RIDD)

  • PIDDosome‐induced p53‐dependent ploidy restriction facilitates hepatocarcinogenesis
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-23
    Valentina C Sladky; Katja Knapp; Tamas G Szabo; Vincent Z Braun; Laura Bongiovanni; Hilda van den Bos; Diana CJ Spierings; Bart Westendorp; Ana Curinha; Tatjana Stojakovic; Hubert Scharnagl; Gerald Timelthaler; Kaoru Tsuchia; Matthias Pinter; Georg Semmler; Floris Foijer; Alain de Bruin; Thomas Reiberger; Nataliya Rohr‐Udilova; Andreas Villunger

    Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. This multi‐protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome deficiency in the

  • Function of the SNARE Ykt6 on autophagosomes requires the Dsl1 complex and the Atg1 kinase complex
    EMBO Rep. (IF 7.497) Pub Date : 2020-10-07
    Jieqiong Gao; Rainer Kurre; Jaqueline Rose; Stefan Walter; Florian Fröhlich; Jacob Piehler; Fulvio Reggiori; Christian Ungermann

    The mechanism and regulation of fusion between autophagosomes and lysosomes/vacuoles are still only partially understood in both yeast and mammals. In yeast, this fusion step requires SNARE proteins, the homotypic vacuole fusion and protein sorting (HOPS) tethering complex, the RAB7 GTPase Ypt7, and its guanine nucleotide exchange factor (GEF) Mon1‐Ccz1. We and others recently identified Ykt6 as the

  • Non‐apoptotic caspase activation preserves Drosophila intestinal progenitor cells in quiescence
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-01
    Lewis Arthurton; Dominik Antoni Nahotko; Jana Alonso; Franz Wendler; Luis Alberto Baena‐Lopez

    Caspase malfunction in stem cells often precedes the appearance and progression of multiple types of cancer, including human colorectal cancer. However, the caspase‐dependent regulation of intestinal stem cell properties remains poorly understood. Here, we demonstrate that Dronc, the Drosophila ortholog of caspase‐9/2 in mammals, limits the number of intestinal progenitor cells and their entry into

  • Zika virus depletes neural stem cells and evades selective autophagy by suppressing the Fanconi anemia protein FANCC
    EMBO Rep. (IF 7.497) Pub Date : 2020-10-19
    Shashi Kant Tiwari; Jason W Dang; Nianwei Lin; Yue Qin; Shaobo Wang; Tariq M Rana

    Zika virus (ZIKV) is an emerging flavivirus, which when passed through vertical transmission from mother to developing fetus can lead to developmental abnormalities, including microcephaly. While there is mounting evidence that suggests a causal relationship between ZIKV infection and microcephaly, the mechanisms by which ZIKV induces these changes remain to be elucidated. Here, we demonstrate that

  • Myf6/MRF4 is a myogenic niche regulator required for the maintenance of the muscle stem cell pool
    EMBO Rep. (IF 7.497) Pub Date : 2020-10-13
    Felicia Lazure; Darren M Blackburn; Aldo H Corchado; Korin Sahinyan; Nabila Karam; Ahmad Sharanek; Duy Nguyen; Christoph Lepper; Hamed S Najafabadi; Theodore J Perkins; Arezu Jahani‐Asl; Vahab D Soleimani

    The function and maintenance of muscle stem cells (MuSCs) are tightly regulated by signals originating from their niche environment. Skeletal myofibers are a principle component of the MuSC niche and are in direct contact with the muscle stem cells. Here, we show that Myf6 establishes a ligand/receptor interaction between muscle stem cells and their associated muscle fibers. Our data show that Myf6

  • Blocking mitochondrial pyruvate import in brown adipocytes induces energy wasting via lipid cycling
    EMBO Rep. (IF 7.497) Pub Date : 2020-12-04
    Michaela Veliova; Caroline M Ferreira; Ilan Y Benador; Anthony E Jones; Kiana Mahdaviani; Alexandra J Brownstein; Brandon R Desousa; Rebeca Acín‐Pérez; Anton Petcherski; Essam A Assali; Linsey Stiles; Ajit S Divakaruni; Marc Prentki; Barbara E Corkey; Marc Liesa; Marcus F Oliveira; Orian S Shirihai

    Combined fatty acid esterification and lipolysis, termed lipid cycling, is an ATP‐consuming process that contributes to energy expenditure. Therefore, interventions that stimulate energy expenditure through lipid cycling are of great interest. Here we find that pharmacological and genetic inhibition of the mitochondrial pyruvate carrier (MPC) in brown adipocytes activates lipid cycling and energy expenditure

  • The tRNA‐like small noncoding RNA mascRNA promotes global protein translation
    EMBO Rep. (IF 7.497) Pub Date : 2020-10-19
    Xinping Lu; Jinliang Huang; Sipeng Wu; Qian Zheng; Peipei Liu; Huimin Feng; Xiaoqing Su; Haipeng Fu; Qiaoran Xi; Geng Wang

    mascRNA is a small cytoplasmic RNA derived from the lncRNA MALAT1. After being processed by the tRNA processing enzymes RNase P and RNase Z, mascRNA undergoes CCA addition like tRNAs and folds into a tRNA‐like cloverleaf structure. While MALAT1 functions in multiple cellular processes, the role of mascRNA was largely unknown. Here, we show that mascRNA binds directly to the multi‐tRNA synthetase complex

  • Class IA PI3Ks regulate subcellular and functional dynamics of IDO1
    EMBO Rep. (IF 7.497) Pub Date : 2020-11-07
    Alberta Iacono; Andrea Pompa; Francesca De Marchis; Eleonora Panfili; Francesco A Greco; Alice Coletti; Ciriana Orabona; Claudia Volpi; Maria L Belladonna; Giada Mondanelli; Elisa Albini; Carmine Vacca; Marco Gargaro; Francesca Fallarino; Roberta Bianchi; Carine De Marcos Lousa; Emilia MC Mazza; Silvio Bicciato; Elisa Proietti; Francesca Milano; Maria P Martelli; Ioana M Iamandii; Mariona Graupera

    Knowledge of a protein’s spatial dynamics at the subcellular level is key to understanding its function(s), interactions, and associated intracellular events. Indoleamine 2,3‐dioxygenase 1 (IDO1) is a cytosolic enzyme that controls immune responses via tryptophan metabolism, mainly through its enzymic activity. When phosphorylated, however, IDO1 acts as a signali