Abstract
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.
Article and author information
Author details
Funding
National Institutes of Health (R35 GM133633)
- Matthew D Daugherty
Pew Charitable Trusts
- Matthew D Daugherty
Hellman Foundation
- Matthew D Daugherty
National Institutes of Health (T32 GM007240)
- Brian V Tsu
- Christopher Beierschmitt
- Andrew P Ryan
National Science Foundation (2019284620)
- Christopher Beierschmitt
Jane Coffin Childs Memorial Fund for Medical Research
- Patrick S Mitchell
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- John W Schoggins, University of Texas Southwestern Medical Center, United States
Publication history
- Received: July 1, 2020
- Accepted: January 6, 2021
- Accepted Manuscript published: January 7, 2021 (version 1)
Copyright
© 2021, Tsu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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