期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 292, 期 50, 页码 20613-20627出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M117.815878
关键词
cell death; cytokine; inflammasome; lipopolysaccharide (LPS); ubiquitylation (ubiquitination); Brucella; caspase-1; caspase-4; pyroptosis
资金
- Department of Biotechnology, Ministry of Science and Technology, Government of India, through the National Institute of Animal Biotechnology, Hyderabad, India
The inflammasome contains intracellular receptors that recognize various pathogen-associated molecular patterns and play crucial roles in innate immune responses to invading pathogens. Non-canonical inflammasome activation is mediated by caspase-4/11, which recognizes intracellular LPS and promotes pyroptosis and secretion of proinflammatory cytokines. Brucella species are infectious intracellular pathogens that replicate in professional and non-professional phagocytic cells and subvert immune responses for chronic persistence in the host. The Brucella effector protein TcpB suppresses Toll-like receptor 2 (TLR2)- and TLR4-mediated innate immune responses by targeted degradation of the Toll/interleukin-1 receptor (TIR) domain-containing adaptor protein. TcpB is a cell-permeable protein with multiple functions, and its intracellular targets other than TIR domain-containing adaptor protein remain unclear. Here, we report that TcpB induces ubiquitination and degradation of the inflammatory caspases 1, 4, and 11. Furthermore, in both mouse and human macrophages, TcpB attenuated LPS-induced non-canonical inflammasome activation and suppressed pyroptosis and secretion of IL-1 and IL-1 induced by intracellular LPS delivery. The intact TIR domain was essential for TcpB to subvert the non-canonical inflammasome activation as a TcpB(G158A) mutant failed to suppress pyroptotic cell death and inflammatory responses. Brucella-infected macrophages exhibited minimal pyroptosis but secreted IL-1, which was suppressed by TcpB. We also demonstrated that TcpB protein can efficiently attenuate Salmonella enterica serovar Typhimurium-induced pyroptosis and proinflammatory cytokine secretion in macrophages. Because TcpB suppresses both TLR4- and caspase-4/11-mediated inflammation, TcpB might be a candidate target for developing drugs against LPS-induced septicemia.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据