A ubiquitin-independent proteasome pathway controls activation of the CARD8 inflammasome

Hsiao, Jeffrey C.; Neugroschl, Atara R; Chui, Ashley J.; Taabuzing, Cornelius Y; Griswold, Andrew R.; Wang, Qinghui; Huang, Hsin-Che; Orth-He, Elizabeth L.; Ball, Daniel P.; Hiotis, Giorgos; Bachovchin, Daniel A.

doi:10.1016/j.jbc.2022.102032

Cited by 13 publications

(7 citation statements)

References 26 publications

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“…We speculate that the core 20 S proteasome, which degrades disordered and misfolded proteins independent of ubiquitin conjugation ( 48 , 49 ), then rapidly destroys the TRX1-free, disordered NLRP1 NT and liberates the NLRP1 CT from autoinhibition. Consistent with this idea, we recently reported that the 20 S proteasome controls the activation of the related CARD8 inflammasome independent of ubiquitination ( 50 ). The details of the NLRP1 degradation process, and whether it involves ubiquitination, require further investigation.…”

Section: Discussionsupporting

confidence: 59%

Oxidized thioredoxin-1 restrains the NLRP1 inflammasome

et al. 2022

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The danger signals that activate the NLRP1 inflammasome have not been established. Here, we report that the oxidized, but not the reduced, form of thioredoxin-1 (TRX1) binds to NLRP1. We found that oxidized TRX1 associates with the NACHT-LRR region of NLRP1 in an ATP-dependent process, forming a stable complex that restrains inflammasome activation. Consistent with these findings, patient-derived and ATPase-inactivating mutations in the NACHT-LRR region that cause hyperactive inflammasome formation interfere with TRX1 binding. Overall, this work strongly suggests that reductive stress, the cellular perturbation that will eliminate oxidized TRX1 and abrogate the TRX1-NLRP1 interaction, is a danger signal that activates the NLRP1 inflammasome.

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Section: Discussionsupporting

confidence: 59%

Oxidized thioredoxin-1 restrains the NLRP1 inflammasome

et al. 2022

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“… 26 These misfolded domains are then destroyed by the ubiquitin-independent core 20S proteasome. 43 We speculate that reductive stress similarly interferes with protein folding. Indeed, oxidative power is critical for protein folding in the ER 44 ; it seems possible that oxidative power plays a similar, but as-yet-unknown, role in the folding of cytosolic proteins, including NLRP1’s and CARD8’s NT fragments.…”

Section: Discussionmentioning

confidence: 92%

The NLRP1 and CARD8 inflammasomes detect reductive stress

et al. 2023

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“…The full-length and FIIND-processed bands are indicated as well as the HIV PR cleavage product. The band at ~45 kDa is the result of cleavage by the 20S proteasome ( Hsiao et al, 2022 ). Middle : Immunoblotting with an anti-p24 gag antibody showing Gag cleavage products p41 gag and p24 gag , and/or full-length Gag, p55 gag .…”

Section: Resultsmentioning

confidence: 99%

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

Kulsuptrakul

Turcotte

Emerman

et al. 2023

eLife

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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.

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A ubiquitin-independent proteasome pathway controls activation of the CARD8 inflammasome

Cited by 13 publications

References 26 publications

Oxidized thioredoxin-1 restrains the NLRP1 inflammasome

Oxidized thioredoxin-1 restrains the NLRP1 inflammasome

The NLRP1 and CARD8 inflammasomes detect reductive stress

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

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