Published online before print August 9, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070220

Accepted for publication June 11, 2007.

Article

Salmonella Effector AvrA Regulation of Colonic Epithelial Cell Inflammation by Deubiquitination

Zhongde Ye^*, Elaine O. Petrof, David Boone, Erika C. Claud, and Jun Sun^¶@

From the Department of Pathology,* The University of Chicago, Chicago, Illinois; the Department of Medicine, Section of Infectious Diseases, The University of Chicago, Chicago, Illinois; The Inflammatory Bowel Disease Research Center, Department of Medicine, The University of Chicago, Chicago, Illinois; the Department of Paediatrics, The University of Chicago Medical Center, Chicago, Illinois; and the Department of Medicine,^¶ Gastroenterology and Hepatology Division, University of Rochester, Rochester, New York

^@ To whom correspondence should be addressed. E-mail: jun_sun{at}urmc.rochester.edu.

	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-B (NF-B) pathway, IB and -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 IB and -catenin in epithelial cells. AvrA deubiquitinates IB, which blocks its degradation and leads to the inhibition of NF-B activation. Target genes of the NF-B pathway, such as interleukin-6, were correspondingly down-regulated during bacterial infection with Salmonella expressing AvrA. AvrA also deubiquitinates and thus blocks degradation of -catenin. Target genes of the -catenin pathway, such as c-myc and cyclinD1, were correspondingly up-regulated with AvrA expression. Increased -catenin further negatively regulates the NF-B pathway. Our findings suggest an important role for AvrA in regulating host inflammatory responses through NF-B and -catenin pathways.

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