TY - JOUR TI - Diverse viral proteases activate the NLRP1 inflammasome AU - Tsu, Brian V AU - Beierschmitt, Christopher AU - Ryan, Andrew P AU - Agarwal, Rimjhim AU - Mitchell, Patrick S AU - Daugherty, Matthew D A2 - Schoggins, John W A2 - Rothlin, Carla V VL - 10 PY - 2021 DA - 2021/01/07 SP - e60609 C1 - eLife 2021;10:e60609 DO - 10.7554/eLife.60609 UR - https://doi.org/10.7554/eLife.60609 AB - The NLRP1 inflammasome is a multiprotein complex that is a potent activator of inflammation. Mouse NLRP1B can be activated through proteolytic cleavage by the bacterial Lethal Toxin (LeTx) protease, resulting in degradation of the N-terminal domains of NLRP1B and liberation of the bioactive C-terminal domain, which includes the caspase activation and recruitment domain (CARD). However, natural pathogen-derived effectors that can activate human NLRP1 have remained unknown. Here, we use an evolutionary model to identify several proteases from diverse picornaviruses that cleave human NLRP1 within a rapidly evolving region of the protein, leading to host-specific and virus-specific activation of the NLRP1 inflammasome. Our work demonstrates that NLRP1 acts as a 'tripwire' to recognize the enzymatic function of a wide range of viral proteases and suggests that host mimicry of viral polyprotein cleavage sites can be an evolutionary strategy to activate a robust inflammatory immune response. KW - host-virus evolution KW - NLRP1 inflammasome KW - effector-triggered immunity KW - picornaviruses KW - pathogen-encoded proteases JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -