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

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.

Structure of the E3 ligase CRL2-ZYG11B with substrates reveals the molecular basis for N-degron recognition and ubiquitination

“…Ubiquitination of the neo-N-terminus of NLRP1 triggers proteasomal degradation and liberation of the CARD-containing C-terminus domain, which self-associates into a filamentous structure capable of activating caspase-1, leading to the release of inflammatory cytokines (e.g., IL-1b and IL-18) and pyroptotic cell death 11,12,17 . A similar activation mechanism of the related CARD8 inflammasome by virus cleavage has also been described 16,[18][19][20][21][22] .…”

CARD8: A Novel Inflammasome Sensor with Well-Known Anti-Inflammatory and Anti-Apoptotic Activity

“…However, as suggested by experiments with T cell receptor-activated and talabostat-treated T cells [ 71 , 72 ], T cell activation abolishes CARD8 function and increases permissiveness to infection [ 75 ]. Interestingly, only CARD8 from humans, but not from primates, contains the Phe59Phe60 motif in the amino-terminus of CARD8 T60 for proteolytic activation by HIV-1 protease, suggesting that this motif emerged after the evolutionary separation of chimpanzees and humans [ 76 ]. Through a similar mechanism, 3CL proteases derived from coronaviruses, including severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), and human rhinovirus (HRV), are able to activate CARD8 in HEK293 and THP-1 cells [ 77 , 78 ].…”