Salmonella secreted factor L deubiquitinase of Salmonella typhimurium inhibits NF-kappaB, suppresses IkappaBalpha ubiquitination and modulates innate immune responses.
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-kappaB activation downstream of IkappaBalpha kinases and impairs IkappaBalpha ubiquitination and degradation, but not IkappaBalpha phosphorylation. Disruption of the gene encoding SseL in S. enterica serovar typhimurium increases IkappaBalpha degradation and ubiquitination, as well as NF-kappaB 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-kappaB-dependent cytokines. Thus, SseL represents one of the first bacterial deubiquitinases demonstrated to modulate the host inflammatory response in vivo.
Le Negrate
Gaëlle
G
Burnham Institute for Medical Research, La Jolla, CA 92037.
Faustin
Benjamin
B
Welsh
Kate
K
Loeffler
Markus
M
Krajewska
Maryla
M
Hasegawa
Patty
P
Mukherjee
Sohini
S
Orth
Kim
K
Krajewski
Stan
S
Godzik
Adam
A
Guiney
Donald G
DG
Reed
John C
JC
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007113:Immunity, Innate / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012486:Salmonella typhimurium / Q000201:enzymology* / Q000276:immunology*; D054875:Ubiquitination
D001426:Bacterial Proteins; D016328:NF-kappa B; D051550:I-kappa B Kinase