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  • 1
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    Mobile genes in the human microbiome are structured from global to individual scales (2016)
    Springer Nature
    In: Nature
    Details
    Publication Date: 2016-07-21
    Description: Mobile genes in the human microbiome are structured from global to individual scales Nature 535, 7612 (2016). doi:10.1038/nature18927 Authors: I. L. Brito, S. Yilmaz, K. Huang, L. Xu, S. D. Jupiter, A. P. Jenkins, W. Naisilisili, M. Tamminen, C. S. Smillie, J. R. Wortman, B. W. Birren, R. J. Xavier, P. C. Blainey, A. K. Singh, D. Gevers & E. J. Alm Recent work has underscored the importance of the microbiome in human health, and has largely attributed differences in phenotype to differences in the species present among individuals. However, mobile genes can confer profoundly different phenotypes on different strains of the same species. Little is known about the function and distribution of mobile genes in the human microbiome, and in particular whether the gene pool is globally homogenous or constrained by human population structure. Here, we investigate this question by comparing the mobile genes found in the microbiomes of 81 metropolitan North Americans with those of 172 agrarian Fiji islanders using a combination of single-cell genomics and metagenomics. We find large differences in mobile gene content between the Fijian and North American microbiomes, with functional variation that mirrors known dietary differences such as the excess of plant-based starch degradation genes found in Fijian individuals. Notably, we also observed differences between the mobile gene pools of neighbouring Fijian villages, even though microbiome composition across villages is similar. Finally, we observe high rates of recombination leading to individual-specific mobile elements, suggesting that the abundance of some genes may reflect environmental selection rather than dispersal limitation. Together, these data support the hypothesis that human activities and behaviours provide selective pressures that shape mobile gene pools, and that acquisition of mobile genes is important for colonizing specific human populations.
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 2
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    Cytokine release and gastrointestinal symptoms after gluten challenge in celiac disease (2019)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2019
    Description: 〈p〉Celiac disease (CeD), caused by immune reactions to cereal gluten, is treated with gluten -elimination diets. Within hours of gluten exposure, either perorally or extraorally by intradermal injection, treated patients experience gastrointestinal symptoms. To test whether gluten exposure leads to systemic cytokine production time -related to symptoms, series of multiplex cytokine measurements were obtained in CeD patients after gluten challenge. Peptide injection elevated at least 15 plasma cytokines, with IL-2, IL-8, and IL-10 being most prominent (fold-change increase at 4 hours of 272, 11, and 1.2, respectively). IL-2 and IL-8 were the only cytokines elevated at 2 hours, preceding onset of symptoms. After gluten ingestion, IL-2 was the earliest and most prominent cytokine (15-fold change at 4 hours). Supported by studies of patient-derived gluten-specific T cell clones and primary lymphocytes, our observations indicate that gluten-specific CD4〈sup〉+〈/sup〉 T cells are rapidly reactivated by antigen -exposure likely causing CeD-associated gastrointestinal symptoms.〈/p〉
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    Genome-wide siRNA screen for mediators of NF-{kappa}B activation [Immunology] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-02-15
    Description: Although canonical NFκB is frequently critical for cell proliferation, survival, or differentiation, NFκB hyperactivation can cause malignant, inflammatory, or autoimmune disorders. Despite intensive study, mammalian NFκB pathway loss-of-function RNAi analyses have been limited to specific protein classes. We therefore undertook a human genome-wide siRNA screen for novel NFκB activation pathway components. Using an Epstein Barr virus latent membrane protein (LMP1) mutant, the transcriptional effects of which are canonical NFκB-dependent, we identified 155 proteins significantly and substantially important for NFκB activation in HEK293 cells. These proteins included many kinases, phosphatases, ubiquitin ligases, and deubiquinating enzymes not previously known to be important for NFκB activation. Relevance to other canonical NFκB pathways was extended by finding that 118 of the 155 LMP1 NF-κB activation pathway components were similarly important for IL-1β–, and 79 for TNFα–mediated NFκB activation in the same cells. MAP3K8, PIM3, and six other enzymes were uniquely relevant to LMP1-mediated NFκB activation. Most novel pathway components functioned upstream of IκB kinase complex (IKK) activation. Robust siRNA knockdown effects were confirmed for all mRNAs or proteins tested. Although multiple ZC3H-family proteins negatively regulate NFκB, ZC3H13 and ZC3H18 were activation pathway components. ZC3H13 was critical for LMP1, TNFα, and IL-1β NFκB-dependent transcription, but not for IKK activation, whereas ZC3H18 was critical for IKK activation. Down-modulators of LMP1 mediated NFκB activation were also identified. These experiments identify multiple targets to inhibit or stimulate LMP1-, IL-1β–, or TNFα–mediated canonical NFκB activation.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Microbiology. How to get along--friendly microbes in a hostile world (2000)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2000-09-19
    Description: Microbiologists have long been puzzled by the finding that the gut mucosa does not respond to the myriad varieties of bacteria that normally reside in the gut. As Xavier and Podolsky explain in their Perspective, this may be because bacteria that are indigenous to the gut have learned ways to switch off pathways in gut epithelial cells that lead to switching on of genes involved in inflammation (Neish et al.).〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xavier, R J -- Podolsky, D K -- New York, N.Y. -- Science. 2000 Sep 1;289(5484):1483-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gastrointestinal Unit, Massachusetts General Hospital, 55 Fruit Street, GRJ-719, Boston, MA 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10991734" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Nucleus/metabolism ; Colon ; Cytokines/genetics ; Cytoplasm/metabolism ; Gene Expression Regulation ; Humans ; I-kappa B Proteins/*metabolism ; Inflammation ; Intestinal Mucosa/*metabolism/*microbiology ; NF-kappa B/*metabolism ; Salmonella/pathogenicity/*physiology ; Tumor Cells, Cultured ; Ubiquitins/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 5
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    RNA interference screen for human genes associated with West Nile virus infection (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-08-12
    Description: West Nile virus (WNV), and related flaviviruses such as tick-borne encephalitis, Japanese encephalitis, yellow fever and dengue viruses, constitute a significant global human health problem. However, our understanding of the molecular interaction of such flaviviruses with mammalian host cells is limited. WNV encodes only 10 proteins, implying that it may use many cellular proteins for infection. WNV enters the cytoplasm through pH-dependent endocytosis, undergoes cycles of translation and replication, assembles progeny virions in association with endoplasmic reticulum, and exits along the secretory pathway. RNA interference (RNAi) presents a powerful forward genetics approach to dissect virus-host cell interactions. Here we report the identification of 305 host proteins that affect WNV infection, using a human-genome-wide RNAi screen. Functional clustering of the genes revealed a complex dependence of this virus on host cell physiology, requiring a wide variety of molecules and cellular pathways for successful infection. We further demonstrate a requirement for the ubiquitin ligase CBLL1 in WNV internalization, a post-entry role for the endoplasmic-reticulum-associated degradation pathway in viral infection, and the monocarboxylic acid transporter MCT4 as a viral replication resistance factor. By extending this study to dengue virus, we show that flaviviruses have both overlapping and unique interaction strategies with host cells. This study provides a comprehensive molecular portrait of WNV-human cell interactions that forms a model for understanding single plus-stranded RNA virus infection, and reveals potential antiviral targets.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136529/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136529/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Krishnan, Manoj N -- Ng, Aylwin -- Sukumaran, Bindu -- Gilfoy, Felicia D -- Uchil, Pradeep D -- Sultana, Hameeda -- Brass, Abraham L -- Adametz, Rachel -- Tsui, Melody -- Qian, Feng -- Montgomery, Ruth R -- Lev, Sima -- Mason, Peter W -- Koski, Raymond A -- Elledge, Stephen J -- Xavier, Ramnik J -- Agaisse, Herve -- Fikrig, Erol -- AI062773/AI/NIAID NIH HHS/ -- AI07526/AI/NIAID NIH HHS/ -- N01 AI500031/AI/NIAID NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-13/DK/NIDDK NIH HHS/ -- R01 AI032947/AI/NIAID NIH HHS/ -- R01 AI041440/AI/NIAID NIH HHS/ -- R01 AI062773/AI/NIAID NIH HHS/ -- R01 AI062773-01A1/AI/NIAID NIH HHS/ -- U01 AI070343/AI/NIAID NIH HHS/ -- U01 AI070343-04/AI/NIAID NIH HHS/ -- U54 AI057156/AI/NIAID NIH HHS/ -- U54 AI057156-01/AI/NIAID NIH HHS/ -- U54 AI057159/AI/NIAID NIH HHS/ -- U54 AI057159-01/AI/NIAID NIH HHS/ -- U54AI057159/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Sep 11;455(7210):242-5. doi: 10.1038/nature07207.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticutt 06520-8031, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18690214" target="_blank"〉PubMed〈/a〉
    Keywords: Computational Biology ; Dengue Virus/physiology ; Endoplasmic Reticulum/metabolism ; Gene Expression Profiling ; Genome, Human ; Hiv ; HeLa Cells ; Humans ; Immunity/genetics ; Monocarboxylic Acid Transporters/deficiency/genetics/metabolism ; Muscle Proteins/deficiency/genetics/metabolism ; Protein Binding ; *RNA Interference ; Ubiquitin-Protein Ligases/deficiency/genetics/metabolism ; Ubiquitination/genetics ; Vesiculovirus ; Virus Replication ; West Nile Fever/*genetics/*virology ; West Nile virus/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 6
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    A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-10-14
    Description: Susceptibility to Crohn's disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci. One Crohn's disease risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG16 (ref. 2). It is not known how ATG16L1 or autophagy contributes to intestinal biology or Crohn's disease pathogenesis. To address these questions, we generated and characterized mice that are hypomorphic for ATG16L1 protein expression, and validated conclusions on the basis of studies in these mice by analysing intestinal tissues that we collected from Crohn's disease patients carrying the Crohn's disease risk allele of ATG16L1. Here we show that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein ATG5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to ATG16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signalling and lipid metabolism, of acute phase reactants and of two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, Crohn's disease patients homozygous for the ATG16L1 Crohn's disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient mice and expressed increased levels of leptin protein. Thus, ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn's disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695978/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695978/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cadwell, Ken -- Liu, John Y -- Brown, Sarah L -- Miyoshi, Hiroyuki -- Loh, Joy -- Lennerz, Jochen K -- Kishi, Chieko -- Kc, Wumesh -- Carrero, Javier A -- Hunt, Steven -- Stone, Christian D -- Brunt, Elizabeth M -- Xavier, Ramnik J -- Sleckman, Barry P -- Li, Ellen -- Mizushima, Noboru -- Stappenbeck, Thaddeus S -- Virgin, Herbert W 4th -- AI062773/AI/NIAID NIH HHS/ -- DK43351/DK/NIDDK NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-13/DK/NIDDK NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- P30 DK043351-18/DK/NIDDK NIH HHS/ -- P30 DK052574-09/DK/NIDDK NIH HHS/ -- P30 DK52574/DK/NIDDK NIH HHS/ -- R01 AI062773/AI/NIAID NIH HHS/ -- R01 AI062773-01A1/AI/NIAID NIH HHS/ -- R01 AI062832/AI/NIAID NIH HHS/ -- R01 AI062832-04/AI/NIAID NIH HHS/ -- T32 AR007279/AR/NIAMS NIH HHS/ -- T32 AR007279-30/AR/NIAMS NIH HHS/ -- T32 AR07279/AR/NIAMS NIH HHS/ -- U54 AI057160/AI/NIAID NIH HHS/ -- U54 AI057160-010005/AI/NIAID NIH HHS/ -- U54 AI057160-05S10018/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Nov 13;456(7219):259-63. doi: 10.1038/nature07416. Epub 2008 Oct 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18849966" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Autophagy/*genetics ; Carrier Proteins/genetics/*metabolism ; Cell Line ; Crohn Disease/genetics/pathology ; Exocytosis/genetics ; Homozygote ; Humans ; Mice ; Mice, Inbred C57BL ; Mutation ; Paneth Cells/*metabolism/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 7
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    Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43 (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-10-30
    Description: The immune system responds to pathogens by a variety of pattern recognition molecules such as the Toll-like receptors (TLRs), which promote recognition of dangerous foreign pathogens. However, recent evidence indicates that normal intestinal microbiota might also positively influence immune responses, and protect against the development of inflammatory diseases. One of these elements may be short-chain fatty acids (SCFAs), which are produced by fermentation of dietary fibre by intestinal microbiota. A feature of human ulcerative colitis and other colitic diseases is a change in 'healthy' microbiota such as Bifidobacterium and Bacteriodes, and a concurrent reduction in SCFAs. Moreover, increased intake of fermentable dietary fibre, or SCFAs, seems to be clinically beneficial in the treatment of colitis. SCFAs bind the G-protein-coupled receptor 43 (GPR43, also known as FFAR2), and here we show that SCFA-GPR43 interactions profoundly affect inflammatory responses. Stimulation of GPR43 by SCFAs was necessary for the normal resolution of certain inflammatory responses, because GPR43-deficient (Gpr43(-/-)) mice showed exacerbated or unresolving inflammation in models of colitis, arthritis and asthma. This seemed to relate to increased production of inflammatory mediators by Gpr43(-/-) immune cells, and increased immune cell recruitment. Germ-free mice, which are devoid of bacteria and express little or no SCFAs, showed a similar dysregulation of certain inflammatory responses. GPR43 binding of SCFAs potentially provides a molecular link between diet, gastrointestinal bacterial metabolism, and immune and inflammatory responses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256734/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256734/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maslowski, Kendle M -- Vieira, Angelica T -- Ng, Aylwin -- Kranich, Jan -- Sierro, Frederic -- Yu, Di -- Schilter, Heidi C -- Rolph, Michael S -- Mackay, Fabienne -- Artis, David -- Xavier, Ramnik J -- Teixeira, Mauro M -- Mackay, Charles R -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-14/DK/NIDDK NIH HHS/ -- R01 AI061570/AI/NIAID NIH HHS/ -- R01 AI061570-06/AI/NIAID NIH HHS/ -- R01 AI074878/AI/NIAID NIH HHS/ -- R01 AI074878-02/AI/NIAID NIH HHS/ -- R01 AI095466/AI/NIAID NIH HHS/ -- R01 HL088297/HL/NHLBI NIH HHS/ -- R01 HL088297-02/HL/NHLBI NIH HHS/ -- England -- Nature. 2009 Oct 29;461(7268):1282-6. doi: 10.1038/nature08530.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19865172" target="_blank"〉PubMed〈/a〉
    Keywords: Acetates/therapeutic use ; Animals ; Arthritis/metabolism ; Cells, Cultured ; Chemotactic Factors/*metabolism ; Colitis/drug therapy/metabolism/microbiology ; Fatty Acids, Volatile/metabolism ; Germ-Free Life ; Humans ; Inflammation/drug therapy/*metabolism/*microbiology ; Intestines/*microbiology ; Metagenome ; Mice ; Mice, Inbred C57BL ; Neutrophils/metabolism ; Oligonucleotide Array Sequence Analysis ; Protein Array Analysis ; Receptors, G-Protein-Coupled/deficiency/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
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    Invertible promoters mediate bacterial phase variation, antibiotic resistance, and host adaptation in the gut (2019)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2019
    Description: 〈p〉Phase variation, the reversible alternation between genetic states, enables infection by pathogens and colonization by commensals. However, the diversity of phase variation remains underexplored. We developed the PhaseFinder algorithm to quantify DNA inversion–mediated phase variation. A systematic search of 54,875 bacterial genomes identified 4686 intergenic invertible DNA regions (invertons), revealing an enrichment in host-associated bacteria. Invertons containing promoters often regulate extracellular products, underscoring the importance of surface diversity for gut colonization. We found invertons containing promoters regulating antibiotic resistance genes that shift to the ON orientation after antibiotic treatment in human metagenomic data and in vitro, thereby mitigating the cost of antibiotic resistance. We observed that the orientations of some invertons diverge after fecal microbiota transplant, potentially as a result of individual-specific selective forces.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
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    Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-03-29
    Description: Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1beta but not tumour-necrosis factor-alpha in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (gamma-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1alpha, an effect that is inhibited by 2-deoxyglucose, with interleukin-1beta as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1beta production during inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031686/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031686/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tannahill, G M -- Curtis, A M -- Adamik, J -- Palsson-McDermott, E M -- McGettrick, A F -- Goel, G -- Frezza, C -- Bernard, N J -- Kelly, B -- Foley, N H -- Zheng, L -- Gardet, A -- Tong, Z -- Jany, S S -- Corr, S C -- Haneklaus, M -- Caffrey, B E -- Pierce, K -- Walmsley, S -- Beasley, F C -- Cummins, E -- Nizet, V -- Whyte, M -- Taylor, C T -- Lin, H -- Masters, S L -- Gottlieb, E -- Kelly, V P -- Clish, C -- Auron, P E -- Xavier, R J -- O'Neill, L A J -- 098516/Wellcome Trust/United Kingdom -- R01 AI093451/AI/NIAID NIH HHS/ -- R56 AI090863/AI/NIAID NIH HHS/ -- U54 AI057153/AI/NIAID NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2013 Apr 11;496(7444):238-42. doi: 10.1038/nature11986. Epub 2013 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23535595" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Marrow Cells/cytology ; Citric Acid Cycle/drug effects ; Deoxyglucose/pharmacology ; Down-Regulation/drug effects ; Genes, Mitochondrial/drug effects/genetics ; Glutamine/metabolism ; Glycolysis/drug effects/genetics ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Immunity, Innate/drug effects ; Inflammation/metabolism ; Interleukin-1beta/*biosynthesis/genetics ; Lipopolysaccharides/pharmacology ; Macrophages/cytology/drug effects/metabolism ; Mice ; *Signal Transduction ; Succinic Acid/*metabolism ; Up-Regulation/drug effects ; gamma-Aminobutyric Acid/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
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    Image-based genome-wide siRNA screen identifies selective autophagy factors (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-10-25
    Description: Selective autophagy involves the recognition and targeting of specific cargo, such as damaged organelles, misfolded proteins, or invading pathogens for lysosomal destruction. Yeast genetic screens have identified proteins required for different forms of selective autophagy, including cytoplasm-to-vacuole targeting, pexophagy and mitophagy, and mammalian genetic screens have identified proteins required for autophagy regulation. However, there have been no systematic approaches to identify molecular determinants of selective autophagy in mammalian cells. Here, to identify mammalian genes required for selective autophagy, we performed a high-content, image-based, genome-wide small interfering RNA screen to detect genes required for the colocalization of Sindbis virus capsid protein with autophagolysosomes. We identified 141 candidate genes required for viral autophagy, which were enriched for cellular pathways related to messenger RNA processing, interferon signalling, vesicle trafficking, cytoskeletal motor function and metabolism. Ninety-six of these genes were also required for Parkin-mediated mitophagy, indicating that common molecular determinants may be involved in autophagic targeting of viral nucleocapsids and autophagic targeting of damaged mitochondria. Murine embryonic fibroblasts lacking one of these gene products, the C2-domain containing protein, SMURF1, are deficient in the autophagosomal targeting of Sindbis and herpes simplex viruses and in the clearance of damaged mitochondria. Moreover, SMURF1-deficient mice accumulate damaged mitochondria in the heart, brain and liver. Thus, our study identifies candidate determinants of selective autophagy, and defines SMURF1 as a newly recognized mediator of both viral autophagy and mitophagy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229641/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229641/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Orvedahl, Anthony -- Sumpter, Rhea Jr -- Xiao, Guanghua -- Ng, Aylwin -- Zou, Zhongju -- Tang, Yi -- Narimatsu, Masahiro -- Gilpin, Christopher -- Sun, Qihua -- Roth, Michael -- Forst, Christian V -- Wrana, Jeffrey L -- Zhang, Ying E -- Luby-Phelps, Katherine -- Xavier, Ramnik J -- Xie, Yang -- Levine, Beth -- AI062773/AI/NIAID NIH HHS/ -- AI109617/AI/NIAID NIH HHS/ -- CA84254/CA/NCI NIH HHS/ -- DK043351/DK/NIDDK NIH HHS/ -- DK086502/DK/NIDDK NIH HHS/ -- DK83756/DK/NIDDK NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-15/DK/NIDDK NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 AI051367/AI/NIAID NIH HHS/ -- R01 AI051367-06/AI/NIAID NIH HHS/ -- UL1 RR024982/RR/NCRR NIH HHS/ -- ZIA BC011168-03/Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Dec 1;480(7375):113-7. doi: 10.1038/nature10546.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9113, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22020285" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy/*genetics ; Capsid Proteins/metabolism ; *Genome-Wide Association Study ; HeLa Cells ; Humans ; Lysosomes/metabolism ; Mice ; Mitochondria/metabolism ; Protein Transport/genetics ; RNA, Small Interfering/*genetics ; Sindbis Virus/metabolism ; Ubiquitin-Protein Ligases/deficiency/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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