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RNA interference screen for human genes associated with West Nile virus infection (2008)

M. N. Krishnan ; A. Ng ; B. Sukumaran ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 455(7210): 242-5. doi: 10.1038/nature07207.

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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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A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells (2008)

K. Cadwell ; J. Y. Liu ; S. L. Brown ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 456(7219): 259-63. doi: 10.1038/nature07416.

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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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Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43 (2009)

K. M. Maslowski ; A. T. Vieira ; A. Ng ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 461(7268): 1282-6. doi: 10.1038/nature08530.

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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

Published by Nature Publishing Group (NPG)

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Identification of host proteins required for HIV infection through a functional genomic screen (2008)

A. L. Brass ; D. M. Dykxhoorn ; Y. Benita ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 319(5865): 921-6. doi: 10.1126/science.1152725.

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Publication Date: 2008-01-12

Description: HIV-1 exploits multiple host proteins during infection. We performed a large-scale small interfering RNA screen to identify host factors required by HIV-1 and identified more than 250 HIV-dependency factors (HDFs). These proteins participate in a broad array of cellular functions and implicate new pathways in the viral life cycle. Further analysis revealed previously unknown roles for retrograde Golgi transport proteins (Rab6 and Vps53) in viral entry, a karyopherin (TNPO3) in viral integration, and the Mediator complex (Med28) in viral transcription. Transcriptional analysis revealed that HDF genes were enriched for high expression in immune cells, suggesting that viruses evolve in host cells that optimally perform the functions required for their life cycle. This effort illustrates the power with which RNA interference and forward genetics can be used to expose the dependencies of human pathogens such as HIV, and in so doing identify potential targets for therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brass, Abraham L -- Dykxhoorn, Derek M -- Benita, Yair -- Yan, Nan -- Engelman, Alan -- Xavier, Ramnik J -- Lieberman, Judy -- Elledge, Stephen J -- AI052014/AI/NIAID NIH HHS/ -- AI062773/AI/NIAID NIH HHS/ -- P30 AI060354/AI/NIAID NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-13/DK/NIDDK NIH HHS/ -- U19-AI056900/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2008 Feb 15;319(5865):921-6. doi: 10.1126/science.1152725. Epub 2008 Jan 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Center for Genetics and Genomics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18187620" target="_blank"〉PubMed〈/a〉

Keywords: Cell Line, Tumor ; Computational Biology ; Cytoskeletal Proteins/genetics/physiology ; Genomics ; HIV Infections/genetics/metabolism/*virology ; HIV-1/genetics/pathogenicity/*physiology ; Host-Pathogen Interactions ; Human Immunodeficiency Virus Proteins/physiology ; Humans ; Intracellular Signaling Peptides and Proteins/genetics/physiology ; Karyopherins/genetics/physiology ; Mediator Complex ; Proteins/*physiology ; RNA Interference ; RNA, Small Interfering ; Transcription, Genetic ; Vesicular Transport Proteins/genetics/physiology ; Virus Integration ; Virus Internalization ; Virus Replication ; rab GTP-Binding Proteins/genetics/physiology

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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Electronic Resource

Unravelling the pathogenesis of inflammatory bowel disease (2007)

Xavier, R. J. ; Podolsky, D. K.

[s.l.] : Nature Publishing Group

Nature 448 (2007), S. 427-434

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ISSN: 1476-4687

Source: Nature Archives 1869 - 2009

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics

Notes: [Auszug] Recently, substantial advances in the understanding of the molecular pathogenesis of inflammatory bowel disease (IBD) have been made owing to three related lines of investigation. First, IBD has been found to be the most tractable of complex disorders for discovering susceptibility genes, and ...

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1038/nature06005

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