The Brucella effector protein TcpB induces degradation of inflammatory caspases and thereby subverts noncanonical inflammasome activation in macrophages [Microbiology]

The inflammasome contains intracellular receptors that recognize various pathogen-associated molecular patterns and play crucial roles in innate immune responses to invading pathogens. Noncanonical 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 nonprofessional 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 TIR domain containing adaptor protein (TIRAP). TcpB is a cell permeable protein with multiple functions, and its intracellular targets other than TIRAP 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 noncanonical inflammasome activation and suppressed pyroptosis and secretion of IL 1 alpha and IL 1 beta; induced by intracellular LPS delivery. The intact TIR domain was essential for TcpB to subvert the noncanonical inflammasome activation, as a TcpBG158A mutant failed to suppress pyroptotic cell death and inflammatory responses. Brucella infected macrophages exhibited minimal pyroptosis but secreted IL 1 beta, which was suppressed by TcpB. We also demonstrated that TcpB protein can efficiently attenuate Salmonella typhimurium induced pyroptosis and proinflammatory cytokine secretion in macrophages. Since TcpB suppresses both TLR4 and caspase 4/11 mediated inflammation, TcpB might be a candidate target for developing drugs against LPS induced septicemia.

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