1. Immunology and Inflammation
  2. Microbiology and Infectious Disease
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Diverse viral proteases activate the NLRP1 inflammasome

  1. Brian V Tsu
  2. Christopher Beierschmitt
  3. Andrew P Ryan
  4. Rimjhim Agarwal
  5. Patrick S Mitchell
  6. Matthew D Daugherty  Is a corresponding author
  1. University of California, San Diego, United States
  2. University of California, Berkeley, United States
Research Article
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Cite this article as: eLife 2021;10:e60609 doi: 10.7554/eLife.60609

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

  1. Brian V Tsu

    Division of Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Christopher Beierschmitt

    Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Andrew P Ryan

    Section of Molecular Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Rimjhim Agarwal

    Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Patrick S Mitchell

    Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Matthew D Daugherty

    Division of Biology, University of California, San Diego, La Jolla, United States
    For correspondence
    mddaugherty@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4879-9603

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

  1. John W Schoggins, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: July 1, 2020
  2. Accepted: January 6, 2021
  3. 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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