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EMBO Reports

Victor L Jensen, Nils J Lambacher, Chunmei Li, Swetha Mohan, Corey L Williams, Peter N Inglis, Bradley K Yoder, Oliver E Blacque, Michel R Leroux
Genetic disorders caused by cilia dysfunction, termed ciliopathies, frequently involve the intraflagellar transport (IFT) system. Mutations in IFT subunits-including IFT-dynein motor DYNC2H1-impair ciliary structures and Hedgehog signalling, typically leading to "skeletal" ciliopathies such as Jeune asphyxiating thoracic dystrophy. Intriguingly, IFT gene mutations also cause eye, kidney and brain ciliopathies often linked to defects in the transition zone (TZ), a ciliary gate implicated in Hedgehog signalling...
November 14, 2018: EMBO Reports
James A Smythies, Min Sun, Norma Masson, Rafik Salama, Peter D Simpson, Elizabeth Murray, Viviana Neumann, Matthew E Cockman, Hani Choudhry, Peter J Ratcliffe, David R Mole
Hypoxia-inducible factor (HIF) is the major transcriptional regulator of cellular responses to hypoxia. The two principal HIF-α isoforms, HIF-1α and HIF-2α, are progressively stabilized in response to hypoxia and form heterodimers with HIF-1β to activate a broad range of transcriptional responses. Here, we report on the pan-genomic distribution of isoform-specific HIF binding in response to hypoxia of varying severity and duration, and in response to genetic ablation of each HIF-α isoform. Our findings reveal that, despite an identical consensus recognition sequence in DNA, each HIF heterodimer loads progressively at a distinct repertoire of cell-type-specific sites across the genome, with little evidence of redistribution under any of the conditions examined...
November 14, 2018: EMBO Reports
Lutz Bornmann, Robin Haunschild
No abstract text is available yet for this article.
November 13, 2018: EMBO Reports
Thomas S van Emden, Marta Forn, Ignasi Forné, Zsuzsa Sarkadi, Matías Capella, Lucía Martín Caballero, Sabine Fischer-Burkart, Cornelia Brönner, Marco Simonetta, David Toczyski, Mario Halic, Axel Imhof, Sigurd Braun
Telomeres and the shelterin complex cap and protect the ends of chromosomes. Telomeres are flanked by the subtelomeric sequences that have also been implicated in telomere regulation, although their role is not well defined. Here, we show that, in Schizosaccharomyces pombe , the telomere-associated sequences (TAS) present on most subtelomeres are hyper-recombinogenic, have metastable nucleosomes, and unusual low levels of H3K9 methylation. Ccq1, a subunit of shelterin, protects TAS from nucleosome loss by recruiting the heterochromatic repressor complexes CLRC and SHREC, thereby linking nucleosome stability to gene silencing...
November 12, 2018: EMBO Reports
Wei-Wei Yan, Yun-Liu Liang, Qi-Xiang Zhang, Di Wang, Ming-Zhu Lei, Jia Qu, Xiang-Huo He, Qun-Ying Lei, Yi-Ping Wang
Sirtuins (SIRTs) are a class of lysine deacylases that regulate cellular metabolism and energy homeostasis. Although sirtuins have been proposed to function in nutrient sensing and signaling, the underlying mechanism remains elusive. SIRT7, a histone H3K18-specific deacetylase, epigenetically controls mitochondria biogenesis, ribosomal biosynthesis, and DNA repair. Here, we report that SIRT7 is methylated at arginine 388 (R388), which inhibits its H3K18 deacetylase activity. Protein arginine methyltransferase 6 (PRMT6) directly interacts with and methylates SIRT7 at R388 in vitro and in vivo R388 methylation suppresses the H3K18 deacetylase activity of SIRT7 without modulating its subcellular localization...
November 12, 2018: EMBO Reports
Sang-Kyu Lee, Woo-Jeong Jeong, Yong-Hee Cho, Pu-Hyeon Cha, Jeong-Su Yoon, Eun Ji Ro, Sooho Choi, Jeong-Min Oh, Yunseok Heo, Hyuntae Kim, Do Sik Min, Gyoonhee Han, Weontae Lee, Kang-Yell Choi
RAS proteins play critical roles in various cellular processes, including growth and transformation. RAS proteins are subjected to protein stability regulation via the Wnt/β-catenin pathway, and glycogen synthase kinase 3 beta (GSK3β) is a key player for the phosphorylation-dependent RAS degradation through proteasomes. GSK3β-mediated RAS degradation does not occur in cells that express a nondegradable mutant (MT) β-catenin. Here, we show that β-catenin directly interacts with RAS at the α-interface region that contains the GSK3β phosphorylation sites, threonine 144 and threonine 148 residues...
November 9, 2018: EMBO Reports
Shinya Oki, Tazro Ohta, Go Shioi, Hideki Hatanaka, Osamu Ogasawara, Yoshihiro Okuda, Hideya Kawaji, Ryo Nakaki, Jun Sese, Chikara Meno
We have fully integrated public chromatin chromatin immunoprecipitation sequencing (ChIP-seq) and DNase-seq data ( n > 70,000) derived from six representative model organisms (human, mouse, rat, fruit fly, nematode, and budding yeast), and have devised a data-mining platform-designated ChIP-Atlas ( ChIP-Atlas is able to show alignment and peak-call results for all public ChIP-seq and DNase-seq data archived in the NCBI Sequence Read Archive (SRA), which encompasses data derived from GEO, ArrayExpress, DDBJ, ENCODE, Roadmap Epigenomics, and the scientific literature...
November 9, 2018: EMBO Reports
Daniel Haensel, Peng Sun, Adam L MacLean, Xianghui Ma, Yuan Zhou, Marc P Stemmler, Simone Brabletz, Geert Berx, Maksim V Plikus, Qing Nie, Thomas Brabletz, Xing Dai
Directional migration is inherently important for epithelial tissue regeneration and repair, but how it is precisely controlled and coordinated with cell proliferation is unclear. Here, we report that Ovol2, a transcriptional repressor that inhibits epithelial-to-mesenchymal transition (EMT), plays a crucial role in adult skin epithelial regeneration and repair. Ovol2 -deficient mice show compromised wound healing characterized by aberrant epidermal cell migration and proliferation, as well as delayed anagen progression characterized by defects in hair follicle matrix cell proliferation and subsequent differentiation...
November 9, 2018: EMBO Reports
Saurabh Shakya, Prerna Sharma, Anshul Milap Bhatt, Riddhi Atul Jani, Cédric Delevoye, Subba Rao Gangi Setty
Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes. However, the mechanism of RE biogenesis is largely unknown. In this study, by using an endosomal Rab-specific RNAi screen, we identified Rab22A as a critical player during RE biogenesis. Rab22A-knockdown results in reduced RE dynamics and concurrent cargo accumulation in the E/SEs or lysosomes...
November 7, 2018: EMBO Reports
Philip Hunter
No abstract text is available yet for this article.
November 7, 2018: EMBO Reports
Shelly Levy-Tzedek, Galia S Moran, Uri Alon, Neta Sal-Man
No abstract text is available yet for this article.
November 5, 2018: EMBO Reports
David Rotter, Heshan Peiris, D Bennett Grinsfelder, Alyce M Martin, Jana Burchfield, Valentina Parra, Christi Hull, Cyndi R Morales, Claire F Jessup, Dusan Matusica, Brian W Parks, Aldons J Lusis, Ngoc Uyen Nhi Nguyen, Misook Oh, Israel Iyoke, Tanvi Jakkampudi, D Randy McMillan, Hesham A Sadek, Matthew J Watt, Rana K Gupta, Melanie A Pritchard, Damien J Keating, Beverly A Rothermel
Increasing non-shivering thermogenesis (NST), which expends calories as heat rather than storing them as fat, is championed as an effective way to combat obesity and metabolic disease. Innate mechanisms constraining the capacity for NST present a fundamental limitation to this approach, yet are not well understood. Here, we provide evidence that Regulator of Calcineurin 1 ( RCAN1 ), a feedback inhibitor of the calcium-activated protein phosphatase calcineurin (CN), acts to suppress two distinctly different mechanisms of non-shivering thermogenesis (NST): one involving the activation of UCP1 expression in white adipose tissue, the other mediated by sarcolipin (SLN) in skeletal muscle...
November 2, 2018: EMBO Reports
Lei Yang, Lishuang Song, Xuefei Liu, Lige Bai, Guangpeng Li
Despite the success of animal cloning by somatic cell nuclear transfer (SCNT) in many species, the method is limited by its low efficiency. After zygotic genome activation (ZGA) during mouse development, a large number of endogenous retroviruses (ERVs) are expressed, including the murine endogenous retrovirus-L (MuERVL/MERVL). In this study, we generate a series of MERVL reporter mouse strains to detect the ZGA event in embryos. We show that the majority of SCNT embryos do not undergo ZGA, and H3K27me3 prevents SCNT reprogramming...
November 2, 2018: EMBO Reports
Andreas Heim, Thomas Tischer, Thomas U Mayer
Vertebrate oocytes await fertilization arrested at metaphase of the second meiotic division. Fertilization triggers a transient calcium wave, which induces the activation of the anaphase-promoting complex/cyclosome (APC/C) and its co-activator Cdc20 resulting in the destruction of cyclin B and hence meiotic exit. Two calcium-dependent enzymes are implicated in fertilization-induced APC/CC dc20 activation: calcium-/calmodulin-dependent kinase type II (CaMKII) and calcineurin (CaN). While the role of CaMKII in targeting the APC/C inhibitor XErp1/Emi2 for destruction is well-established, it remained elusive how CaN affects APC/CC dc20 activation...
October 29, 2018: EMBO Reports
Alessandro Torgovnick, Alfonso Schiavi, Anjumara Shaik, Henok Kassahun, Silvia Maglioni, Shane L Rea, Thomas E Johnson, Hans C Reinhardt, Sebastian Honnen, Björn Schumacher, Hilde Nilsen, Natascia Ventura
Interventions that promote healthy aging are typically associated with increased stress resistance. Paradoxically, reducing the activity of core biological processes such as mitochondrial or insulin metabolism promotes the expression of adaptive responses, which in turn increase animal longevity and resistance to stress. In this study, we investigated the relation between the extended Caenorhabditis elegans lifespan elicited by reduction in mitochondrial functionality and resistance to genotoxic stress. We find that reducing mitochondrial activity during development confers germline resistance to DNA damage-induced cell cycle arrest and apoptosis in a cell-non-autonomous manner...
October 26, 2018: EMBO Reports
Taisuke Nakahama, Yuki Kato, Jung In Kim, Tuangtong Vongpipatana, Yutaka Suzuki, Carl R Walkley, Yukio Kawahara
T cells play a crucial role in the adaptive immune system, and their maturation process is tightly regulated. Adenosine deaminase acting on RNA 1 (ADAR1) is the enzyme responsible for adenosine-to-inosine RNA editing in dsRNAs, and loss of ADAR1 activates the innate immune sensing response via melanoma differentiation-associated protein 5 (MDA5), which interprets unedited dsRNA as non-self. Although ADAR1 is highly expressed in the thymus, its role in the adaptive immune system, especially in T cells, remains elusive...
October 25, 2018: EMBO Reports
Saviz Ehyai, Tetsuaki Miyake, Declan Williams, Jyotsna Vinayak, Mark A Bayfield, John C McDermott
Canonical Wnt/β-catenin signaling is an essential regulator of various cellular functions throughout development and adulthood. Aberrant Wnt/β-catenin signaling also contributes to various pathologies including cancer, necessitating an understanding of cell context-dependent mechanisms regulating this pathway. Since protein-protein interactions underpin β-catenin function and localization, we sought to identify novel β-catenin interacting partners by affinity purification coupled with tandem mass spectrometry in vascular smooth muscle cells (VSMCs), where β-catenin is involved in both physiological and pathological control of cell proliferation...
October 25, 2018: EMBO Reports
Sungkyu Lee, Kyungsoo Park, Jieun Kim, Hyungyu Min, Rho H Seong
Proper control of immune responses by Foxp3+ regulatory T cells at inflamed sites is crucial for the prevention of immunopathology. TGF-β-induced Foxp3+ regulatory T (Treg ) cells are generated in inflammatory environments as well as in steady-state conditions. Inflammatory cytokines such as IFN-γ and IL-4 have an antagonistic effect on Treg cell conversion. However, it is not known how naive CD4+ T cells overcome the inhibitory environment in inflamed sites to differentiate into Treg cells. Here, we show that CCAAT/enhancer-binding protein (C/EBP) functions as a safeguard that enhances Treg cell generation by dampening the inhibitory effect of IFN-γ and IL-4 on Foxp3 expression...
October 22, 2018: EMBO Reports
Katharina Fuchs, Yamel Cardona Gloria, Olaf-Oliver Wolz, Franziska Herster, Lokesh Sharma, Carly A Dillen, Christoph Täumer, Sabine Dickhöfer, Zsofia Bittner, Truong-Minh Dang, Anurag Singh, Daniel Haischer, Maria A Schlöffel, Kirsten J Koymans, Tharmila Sanmuganantham, Milena Krach, Thierry Roger, Didier Le Roy, Nadine A Schilling, Felix Frauhammer, Lloyd S Miller, Thorsten Nürnberger, Salomé LeibundGut-Landmann, Andrea A Gust, Boris Macek, Martin Frank, Cécile Gouttefangeas, Charles S Dela Cruz, Dominik Hartl, Alexander Nr Weber
Chitin is the second most abundant polysaccharide in nature and linked to fungal infection and asthma. However, bona fide immune receptors directly binding chitin and signaling immune activation and inflammation have not been clearly identified because polymeric crude chitin with unknown purity and molecular composition has been used. By using defined chitin (N-acetyl-glucosamine) oligomers, we here identify six-subunit-long chitin chains as the smallest immunologically active motif and the innate immune receptor Toll-like receptor (TLR2) as a primary fungal chitin sensor on human and murine immune cells...
October 18, 2018: EMBO Reports
Norihiko Furuya, Soichiro Kakuta, Katsuhiko Sumiyoshi, Maya Ando, Risa Nonaka, Ayami Suzuki, Saiko Kazuno, Shinji Saiki, Nobutaka Hattori
Parkin-mediated mitophagy is a quality control pathway that selectively removes damaged mitochondria via the autophagic machinery. Autophagic receptors, which interact with ubiquitin and Atg8 family proteins, contribute to the recognition of damaged mitochondria by autophagosomes. NDP52, an autophagy receptor, is required for autophagic engulfment of damaged mitochondria during mitochondrial uncoupler treatment. The N-terminal SKICH domain and C-terminal zinc finger motif of NDP52 are both required for its function in mitophagy...
October 11, 2018: EMBO Reports
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