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Nature Cell Biology

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https://www.readbyqxmd.com/read/28920955/mir-25-93-mediates-hypoxia-induced-immunosuppression-by-repressing-cgas
#1
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
The mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA...
September 18, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28920954/p38-mapk-mk2-dependent-phosphorylation-controls-cytotoxic-ripk1-signalling-in-inflammation-and%C3%A2-infection
#2
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
Receptor-interacting protein kinase-1 (RIPK1), a master regulator of cell fate decisions, was identified as a direct substrate of MAPKAP kinase-2 (MK2) by phosphoproteomic screens using LPS-treated macrophages and stress-stimulated embryonic fibroblasts. p38(MAPK)/MK2 interact with RIPK1 in a cytoplasmic complex and MK2 phosphorylates mouse RIPK1 at Ser321/336 in response to pro-inflammatory stimuli, such as TNF and LPS, and infection with the pathogen Yersinia enterocolitica. MK2 phosphorylation inhibits RIPK1 autophosphorylation, curtails RIPK1 integration into cytoplasmic cytotoxic complexes, and suppresses RIPK1-dependent apoptosis and necroptosis...
September 18, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28920953/lifelong-haematopoiesis-is-established-by-hundreds-of-precursors-throughout-mammalian-ontogeny
#3
Miguel Ganuza, Trent Hall, David Finkelstein, Ashley Chabot, Guolian Kang, Shannon McKinney-Freeman
Current dogma asserts that mammalian lifelong blood production is established by a small number of blood progenitors. However, this model is based on assays that require the disruption, transplantation and/or culture of embryonic tissues. Here, we used the sample-to-sample variance of a multicoloured lineage trace reporter to assess the frequency of emerging lifelong blood progenitors while avoiding the disruption, culture or transplantation of embryos. We find that approximately 719 Flk1(+) mesodermal precursors, 633 VE-cadherin(+) endothelial precursors and 545 Vav1(+) nascent blood stem and progenitor cells emerge to establish the haematopoietic system at embryonic days (E)7-E8...
September 18, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28920952/mk2-phosphorylation-of-ripk1-regulates-tnf-mediated-cell-death
#4
Yves Dondelinger, Tom Delanghe, Diego Rojas-Rivera, Dario Priem, Tinneke Delvaeye, Inge Bruggeman, Franky Van Herreweghe, Peter Vandenabeele, Mathieu J M Bertrand
TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis...
September 18, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28892082/myofibril-contraction-and-crosslinking-drive-nuclear-movement-to-the-periphery-of-skeletal-muscle
#5
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...
September 11, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28892081/a20-promotes-metastasis-of-aggressive-basal-like-breast-cancers-through-multi-monoubiquitylation-of%C3%A2-snail1
#6
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...
September 11, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28892080/differential-effects-on-lung-and-bone-metastasis-of-breast-cancer-by-wnt-signalling-inhibitor-dkk1
#7
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/Ca(2+)-CaMKII-NF-κB signalling and suppresses LTBP1-mediated TGF-β secretion of cancer cells...
September 11, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28892079/retriever-is-a-multiprotein-complex-for-retromer-independent-endosomal-cargo-recycling
#8
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...
September 11, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28846094/reversible-protein-aggregation-is-a-protective-mechanism-to-ensure-cell-cycle-restart-after-stress
#9
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...
August 28, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28846093/super-resolution-microscopy-reveals-that-disruption-of-ciliary-transition-zone-architecture-causes-joubert%C3%A2-syndrome
#10
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...
August 28, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28812582/control-of-intestinal-stem-cell-function-and-proliferation-by-mitochondrial-pyruvate-metabolism
#11
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...
August 14, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28812581/nfia-co-localizes-with-ppar%C3%AE-and-transcriptionally-controls-the-brown-fat-gene-program
#12
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...
August 14, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28812580/lactate-dehydrogenase-activity-drives-hair-follicle-stem-cell-activation
#13
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...
August 14, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28846096/mitochondrial-permeabilization-engages-nf-%C3%AE%C2%BAb-dependent-anti-tumour-activity-under-caspase%C3%A2-deficiency
#14
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...
September 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28846095/zscan10-expression-corrects-the-genomic-instability-of-ipscs-from-aged-donors
#15
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...
September 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28825700/smc-complexes-differentially-compact-mitotic-chromosomes-according-to-genomic-context
#16
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...
September 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28825699/an-apical-mrck-driven-morphogenetic-pathway-controls-epithelial-polarity
#17
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...
September 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28825698/a-regulated-pnuts-mrna-to-lncrna-splice-switch-mediates-emt-and-tumour-progression
#18
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...
September 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28825697/early-loss-of-crebbp-confers-malignant-stem-cell-properties-on-lymphoid-progenitors
#19
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...
September 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28759028/innate-immune-sensing-of-cytosolic-chromatin-fragments-through-cgas-promotes-senescence
#20
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...
September 2017: Nature Cell Biology
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