Activation of the CARD8 inflammasome requires a disordered region Journal Article
| Authors: | Chui, A. J.; Griswold, A. R.; Taabazuing, C. Y.; Orth, E. L.; Gai, K.; Rao, S. D.; Ball, D. P.; Hsiao, J. C.; Bachovchin, D. A. |
| Article Title: | Activation of the CARD8 inflammasome requires a disordered region |
| Abstract: | Several cytosolic pattern-recognition receptors (PRRs) form multiprotein complexes called canonical inflammasomes in response to intracellular danger signals. Canonical inflammasomes recruit and activate caspase-1 (CASP1), which in turn cleaves and activates inflammatory cytokines and gasdermin D (GSDMD), inducing pyroptotic cell death. Inhibitors of the dipeptidyl peptidases DPP8 and DPP9 (DPP8/9) activate both the human NLRP1 and CARD8 inflammasomes. NLRP1 and CARD8 have different N-terminal regions but have similar C-terminal regions that undergo autoproteolysis to generate two non-covalently associated fragments. Here, we show that DPP8/9 inhibition activates a proteasomal degradation pathway that targets disordered and misfolded proteins for destruction. CARD8's N terminus contains a disordered region of ∼160 amino acids that is recognized and destroyed by this degradation pathway, thereby freeing its C-terminal fragment to activate CASP1 and induce pyroptosis. Thus, CARD8 serves as an alarm to signal the activation of a degradation pathway for disordered and misfolded proteins. © 2020 Inflammasomes are multiprotein complexes that detect intracellular danger signals and stimulate powerful immune responses. DPP8/9 inhibitors activate the CARD8 inflammasome through an unknown mechanism. Here, Chui et al. show that DPP8/9 inhibitors induce the degradation of many disordered and misfolded proteins. CARD8 has an N-terminal disordered region that is degraded upon DPP8/9 inhibition, triggering inflammasome formation. © 2020 |
| Keywords: | proteasome; inflammasomes; dpp8/9; val-boropro; card8; protein disorder |
| Journal Title: | Cell Reports |
| Volume: | 33 |
| Issue: | 2 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2020-10-13 |
| Start Page: | 108264 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2020.108264 |
| PUBMED: | 33053349 |
| PROVIDER: | scopus |
| PMCID: | PMC7594595 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 November 2020 -- Source: Scopus |
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