Salmonella secreted factor l deubiquitinase of Salmonella typhimurium inhibits NF-κB, Suppresses IkBαUbiquitination and modulates innate immune responses

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

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Abstract

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-κB activation downstream of IkBα kinases and impairs IkBα ubiquitination and degradation, but not IkBα phosphorylation. Disruption of the gene encoding SseL in S. enterica serovar typhimurium increases IkBα degradation and ubiquitination, as well as NF-κB 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-κB-dependent cytokines. Thus, SseL represents one of the first bacterial deubiquitinases demonstrated to modulate the host inflammatory response in vivo.

Original languageEnglish (US)
Pages (from-to)5045-5056
Number of pages12
JournalJournal of Immunology
Volume180
Issue number7
StatePublished - Apr 1 2008

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ASJC Scopus subject areas

  • Immunology

Cite this

Negrate, G. L., Faustin, B., Welsh, K., Loeffler, M., Krajewska, M., Hasegawa, P., Mukherjee, S., Orth, K., Krajewski, S., Godzik, A., Guiney, D. G., & Reed, J. C. (2008). Salmonella secreted factor l deubiquitinase of Salmonella typhimurium inhibits NF-κB, Suppresses IkBαUbiquitination and modulates innate immune responses. Journal of Immunology, 180(7), 5045-5056.