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Jakka, Padmaja and Namani, Swapna and Murugan, Subathra and Rai, Nivedita and Radhakrishnan, Girish (2017) TheBrucellaeffector protein TcpB induces degradation of inflammatory caspases and thereby subverts non-canonical inflammasome activation in macrophages. Journal of Biological Chemistry, 292 (50). pp. 20613-20627. ISSN 0021-9258

J. Biol. Chem.-2017-Jakka-jbc.M117.815878.pdf

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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-1α and IL-1β 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-1β, 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.

Item Type: Article
Subjects: Animal Genetics and Genomics
Depositing User: Mr Harjit Singh
Date Deposited: 22 Nov 2018 06:51
Last Modified: 24 Apr 2019 05:57
URI: http://niab.sciencecentral.in/id/eprint/42

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