A human-specific motif facilitates CARD8 inflammasome activation after HIV-1 infection
- University of Washington, United States
- University of California, Berkeley, United States
- Fred Hutchinson Cancer Research Center, United States
Abstract
Inflammasomes are cytosolic innate immune complexes that assemble upon detection of diverse pathogen-associated cues and play a critical role in host defense and inflammatory pathogenesis. Here, we find that the human inflammasome-forming sensor CARD8 senses HIV-1 infection via site-specific cleavage of the CARD8 N-terminus by the HIV protease (HIV-1PR). HIV-1PR cleavage of CARD8 induces pyroptotic cell death and the release of pro-inflammatory cytokines from infected cells, processes regulated by Toll-like receptor stimulation prior to viral infection. In acutely infected cells, CARD8 senses the activity of both de novo translated and packaged HIV-1PR that is released from the incoming virion. Moreover, our evolutionary analyses reveal that the HIV-1PR cleavage site in human CARD8 arose after the divergence of chimpanzees and humans. Although chimpanzee CARD8 does not recognize proteases from HIV or simian immunodeficiency viruses from chimpanzees (SIVcpz), SIVcpz doescleave human CARD8, suggesting that SIVcpz was poised to activate the human CARD8 inflammasome prior to its cross-species transmission into humans. Our findings suggest a unique role for CARD8 inflammasome activation in response to lentiviral infection of humans.
Data availability
All data generated or analyzed during this study are included in the manuscript, Figure 3-source data, Figure 3 - Supplement 1-source data, Figure 4-source data, Figure 5 - Supplement 1-source data, and Figure 1-5-source data, including raw tiffs and uncropped blots.
Article and author information
Author details
Jessie Kulsuptrakul
Patrick S Mitchell
Funding
National Institute of Allergy and Infectious Diseases (DP2 AI 154432-01)
- Patrick S Mitchell
Edward Mallinckrodt, Jr. Foundation (Grant)
- Patrick S Mitchell
National Institute on Drug Abuse (DP1 DA051110)
- Michael Emerman
National Institute of General Medical Sciences (T32 GM007270)
- Jessie Kulsuptrakul
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Frank Kirchhoff, Ulm University Medical Center, Germany
Version history
- Preprint posted: October 4, 2022 (view preprint)
- Received: October 12, 2022
- Accepted: July 6, 2023
- Accepted Manuscript published: July 7, 2023 (version 1)
- Version of Record published: July 20, 2023 (version 2)
Copyright
© 2023, Kulsuptrakul 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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A human-specific motif facilitates CARD8 inflammasome activation after HIV-1 infection
eLife 12:e84108.
https://doi.org/10.7554/eLife.84108
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