Journal
NATURE
Volume 592, Issue 7856, Pages 778-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41586-021-03350-4
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Funding
- National Cancer Institute's National Cryo-EM Facility at the Frederick National Laboratory for Cancer Research [HSSN261200800001E]
- Office of Biological and Environmental Research
- National Institutes of Health
- Cancer Research Institute [DP1 HD087988, R01 AI124491, T32-GM007726]
- Cancer Research Institute (CRI Irvington Postdoctoral Fellowship) [R01GM132129, R01GM67945, T32 GM007739, F30 CA243444]
- Cancer Research Institute (Memorial Sloan Kettering Cancer Center Core Grant) [P30 CA008748, R01 AI137168]
- NIH [U24GM129547]
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NLRP1 is an inflammasome sensor that mediates caspase-1 activation, and its function is regulated by DPP8/DPP9, with VbP disrupting the NLRP1-DPP9 interaction to accelerate inflammasome activation.
Nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 1 (NLRP1) is an inflammasome sensor that mediates the activation of caspase-1 to induce cytokine maturation and pyroptosis(1-4). Gain-of-function mutations of NLRP1 cause severe inflammatory diseases of the skin(4-6). NLRP1 contains a function-to-find domain that auto-proteolyses into noncovalently associated subdomains(7-9), and proteasomal degradation of the repressive N-terminal fragment of NLRP1 releases its inflammatory C-terminal fragment (NLRP1 CT)(10,11). Cytosolic dipeptidyl peptidases 8 and 9 (hereafter, DPP8/DPP9) both interact with NLRP1, and small-molecule inhibitors of DPP8/DPP9 activate NLRP1 by mechanisms that are currently unclear(10,12-14). Here we report cryo-electron microscopy structures of the human NLRP1-DPP9 complex alone and with Val-boroPro (VbP), an inhibitor of DPP8/DPP9. The structures reveal a ternary complex that comprises DPP9, full-length NLRP1 and the NLRPT CT. The binding of the NLRP1 CT to DPP9 requires full-length NLRP1, which suggests that NLRP1 activation is regulated by the ratio of NLRP1 CT to full-length NLRP1. Activation of the inflammasome by ectopic expression of the NLRP1 CT is consistently rescued by co-expression of autoproteolysis-deficient full-length NLRP1. The N terminus of the NLRP1 CT inserts into the DPP9 active site, and VbP disrupts this interaction. Thus, VbP weakens the NLRP1-DPP9 interaction and accelerates degradation of the N-terminal fragment(10) to induce inflammasome activation. Overall, these data demonstrate that DPP9 quenches low levels of NLRP1 CT and thus serves as a checkpoint for activation of the NLRP1 inflammasome.
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