TY - JOUR
T1 - Salmonella secreted factor l deubiquitinase of Salmonella typhimurium inhibits NF-κB, Suppresses IkBαUbiquitination and modulates innate immune responses
AU - Negrate, Gaeile Le
AU - Faustin, Benjamin
AU - Welsh, Kate
AU - Loeffler, Markus
AU - Krajewska, Maryla
AU - Hasegawa, Patty
AU - Mukherjee, Sohini
AU - Orth, Kim
AU - Krajewski, Stan
AU - Godzik, Adam
AU - Guiney, Donald G.
AU - Reed, John C.
PY - 2008/4/1
Y1 - 2008/4/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.180.7.5045
DO - 10.4049/jimmunol.180.7.5045
M3 - Article
C2 - 18354230
AN - SCOPUS:44449107633
SN - 0022-1767
VL - 180
SP - 5045
EP - 5056
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -