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Salmonella Secreted Factor L Deubiquitinase of Salmonella typhimurium Inhibits NF-B, Suppresses IB Ubiquitination and Modulates Innate Immune Responses¹

Gaëlle Le Negrate^*, Benjamin Faustin^*, Kate Welsh^*, Markus Loeffler^*, Maryla Krajewska^*, Patty Hasegawa, Sohini Mukherjee, Kim Orth, Stan Krajewski^*, Adam Godzik^*, Donald G. Guiney and John C. Reed^2,*

^* Burnham Institute for Medical Research, La Jolla, CA 92037; Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093; and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390

Salmonella enterica translocates virulent factors into host cells using type III secretion systems to promote host colonization, intracellular bacterial replication and survival, and disease pathogenesis. Among many effectors, the type III secretion system encoded in Salmonella pathogenicity island 2 translocates a Salmonella-specific protein, designated Salmonella secreted factor L (SseL), a putative virulence factor possessing deubiquitinase activity. In this study, we attempt to elucidate the mechanism and the function of SseL in vitro, in primary host macrophages and in vivo in infected mice. Expression of SseL in mammalian cells suppresses NF-B activation downstream of IB kinases and impairs IB ubiquitination and degradation, but not IB phosphorylation. Disruption of the gene encoding SseL in S. enterica serovar typhimurium increases IB degradation and ubiquitination, as well as NF-B activation in infected macrophages, compared with wild-type bacteria. Mice infected with SseL-deficient bacteria mount stronger inflammatory responses, associated with increased production of NF-B-dependent cytokines. Thus, SseL represents one of the first bacterial deubiquitinases demonstrated to modulate the host inflammatory response in vivo.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Crohn’s and Colitis Foundation of America, Association de la Recherche contre le Cancer, and National Institutes of Health AI-055789 and AI-32178.

² Address correspondence and reprint requests to Dr. John C. Reed, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: reedoffice{at}burnham.org

³ Abbreviations used in this paper: IKK, IB kinase; SCF, stem cell factor; DUB, deubiquitinating enzyme; WT, wild type; SseL, Salmonella secreted factor L; LB, Luria-Bertani; Kan, kanamycin; HA, hemagglutinin; PARP, poly(ADP-ribose) polymerase; IP, immunoprecipitation; p.i., postinfection; AMC, 7-amino-4-methylcoumarin; PMN, polymorphonuclear neutrophil; m.o.i., multiplicity of infection; hsp, heat shock protein; SUMO, small ubiquitin-related modifier; NEDD8, neural precursor cell-expressed developmentally down-regulated 8.