title: Salmonella effector AvrA regulation of colonic epithelial cell inflammation by deubiquitination.
abstract: AvrA is a newly described bacterial effector existing in Salmonella. Here, we test the hypothesis that AvrA is a deubiquitinase that removes ubiquitin from two inhibitors of the nuclear factor-kappaB (NF-kappaB) pathway, IkappaBalpha and beta-catenin, thereby inhibiting the inflammatory responses of the host. The role of AvrA was assessed in intestinal epithelial cell models and in mouse models infected with AvrA-deficient and -sufficient Salmonella strains. We also purified AvrA and AvrA mutant proteins and characterized their deubiquitinase activity in a cell-free system. We investigated target gene and inflammatory cytokine expression, as well as effects on epithelial cell proliferation and apoptosis induced by AvrA-deficient and -sufficient bacterial strains in vivo. Our results show that AvrA blocks degradation of IkappaBalpha and beta-catenin in epithelial cells. AvrA deubiquitinates IkappaBalpha, which blocks its degradation and leads to the inhibition of NF-kappaB activation. Target genes of the NF-kappaB pathway, such as interleukin-6, were correspondingly down-regulated during bacterial infection with Salmonella expressing AvrA. AvrA also deubiquitinates and thus blocks degradation of beta-catenin. Target genes of the beta-catenin pathway, such as c-myc and cyclinD1, were correspondingly up-regulated with AvrA expression. Increased beta-catenin further negatively regulates the NF-kappaB pathway. Our findings suggest an important role for AvrA in regulating host inflammatory responses through NF-kappaB and beta-catenin pathways.
authors: Department of Pathology, The University of Chicago, Chicago, Illinois, USA.
authors: Zhongde
authors: Z
authors: Ye
authors: Elaine O
authors: EO
authors: Petrof
authors: David
authors: D
authors: Boone
authors: Erika C
authors: EC
authors: Claud
authors: Jun
authors: J
authors: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D003106:Colon / Q000166:cytology*; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012481:Salmonella Infections, Animal / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C487891:AvrA protein, Salmonella typhimurium; D001426:Bacterial Proteins; D056741:Cyclin D; D016213:Cyclins; D020672:I-kappa B Proteins; C489428:Myc protein, mouse; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D025801:Ubiquitin; D051176:beta Catenin; D000072000:NF-KappaB Inhibitor alpha
references: Lab Invest. 2007 Jun;87(6):613-24
references: 17384665
references: Mol Carcinog. 2004 Mar;39(3):139-46
references: 14991743
references: Bioessays. 1999 Dec;21(12):1021-30
references: 10580987
references: J Immunol. 2000 Jan 15;164(2):966-72
references: 10623846
references: Biochem Biophys Res Commun. 2000 Aug 11;274(3):576-82
references: 10924320
references: Science. 2000 Sep 1;289(5484):1560-3
references: 10968793
references: Gastroenterology. 2000 Oct;119(4):1007-18
references: 11040187
references: Science. 2000 Nov 24;290(5496):1594-7
references: 11090361
references: J Immunol. 2001 Aug 15;167(4):1882-5
references: 11489966
references: Nat Immunol. 2002 Mar;3(3):221-7
references: 11875461
references: Arch Biochem Biophys. 2002 Apr 1;400(1):76-84
references: 11913973
references: J Biol Chem. 2002 Apr 12;277(15):13346-53
references: 11821427
references: J Immunol. 2002 Sep 15;169(6):2846-50
references: 12218096
references: Cancer Cell. 2002 Oct;2(4):323-34
references: 12398896
references: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15572-6
references: 14663138
references: Science. 2006 May 26;312(5777):1211-4
references: 16728640
references: Trends Immunol. 2004 Jun;25(6):280-8
references: 15145317
references: Am J Physiol Gastrointest Liver Physiol. 2004 Jul;287(1):G220-7
references: 14764450
references: Nat Immunol. 2004 Oct;5(10):1052-60
references: 15334086
references: J Bacteriol. 1990 May;172(5):2485-90
references: 2185222
references: J Cell Biol. 1993 Nov;123(4):895-907
references: 8227148
references: Infect Immun. 1997 Jan;65(1):24-34
references: 8975888
references: Science. 1997 Mar 21;275(5307):1787-90
references: 9065402
references: Science. 1998 Sep 4;281(5382):1509-12
references: 9727977
references: Genes Dev. 1999 Feb 1;13(3):270-83
references: 9990852
references: Mol Nutr Food Res. 2004 Dec;48(7):496-503
references: 15538712
references: Am J Physiol Gastrointest Liver Physiol. 2005 Jul;289(1):G129-37
references: 15790758
references: J Exp Med. 2005 Nov 21;202(10):1327-32
references: 16301742
references: Cell. 2006 Feb 24;124(4):767-82
references: 16497587
references: Am J Physiol Gastrointest Liver Physiol. 2006 Apr;290(4):G685-94
references: 16322091