The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1.
Recently, Salmonella spp. were shown to induce apoptosis in infected macrophages. The mechanism responsible for this process is unknown. In this report, we establish that the Inv-Spa type III secretion apparatus target invasin SipB is necessary and sufficient for the induction of apoptosis. Purified SipB microinjected into macrophages led to cell death. Binding studies show that SipB associates with the proapoptotic protease caspase-1. This interaction results in the activation of caspase-1, as seen in its proteolytic maturation and the processing of its substrate interleukin-1beta. Caspase-1 activity is essential for the cytotoxicity. Functional inhibition of caspase-1 activity by acetyl-Tyr-Val-Ala-Asp-chloromethyl ketone blocks macrophage cytotoxicity, and macrophages lacking caspase-1 are not susceptible to Salmonella-induced apoptosis. Taken together, the data demonstrate that SipB functions as an analog of the Shigella invasin IpaB.
Skirball Institute, Department of Microbiology and Kaplan Cancer Center, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
D
D
Hersh
D M
DM
Monack
M R
MR
Smith
N
N
Ghori
S
S
Falkow
A
A
Zychlinsky
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000235:genetics / Q000633:toxicity*; D020170:Caspase 1 / Q000172:deficiency / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008565:Membrane Proteins / Q000008:administration & dosage / Q000235:genetics / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections; D016254:Mutagenesis, Insertional; D011485:Protein Binding; D012475:Salmonella / Q000235:genetics / Q000472:pathogenicity*; D012485:Salmonella typhi / Q000472:pathogenicity; D012486:Salmonella typhimurium / Q000472:pathogenicity
D001426:Bacterial Proteins; D008565:Membrane Proteins; C094579:invasion protein B, Salmonella typhimurium; D020170:Caspase 1