A human-specific motif facilitates CARD8 inflammasome activation after HIV-1 infection

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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-1^PR). HIV-1^PR 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-1^PR that is released from the incoming virion. Moreover, our evolutionary analyses reveal that the HIV-1^PR 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.

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Jessie Kulsuptrakul

Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3881-4686
Elizabeth A Turcotte

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Michael Emerman

Divisions of Human Biology and Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States

For correspondence
memerman@fredhutch.org

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4181-6335
Patrick S Mitchell

Department of Microbiology, University of Washington, Seattle, United States

For correspondence
psmitche@uw.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8375-9060

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.

Copyright

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.