Research ArticleINFLAMMATION

Pharmacological targeting of NLRP3 deubiquitination for treatment of NLRP3-associated inflammatory diseases

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Science Immunology  30 Apr 2021:
Vol. 6, Issue 58, eabe2933
DOI: 10.1126/sciimmunol.abe2933

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DUBbing new inflammasome inhibitors

Inflammasome assembly and activation leading to mature IL-1β release is dysregulated in a wide range of inflammatory diseases. Optimal activation of the NLRP3 inflammasome requires the activity of BRISC, a deubiquitinating enzyme (DUB) complex composed of four protein subunits including BRCC3. Ren et al. demonstrate that the compound thiolutin, a zinc chelator that inhibits JAMM domain–containing metalloproteases including BRCC3, can potently inhibit NLRP3 deubiquitination and inflammasome activation. Thiolutin was effective at inhibiting NLRP3 activation and preventing IL-1β production in multiple mouse models of inflammatory disease, including a model of diet-induced nonalcoholic fatty liver disease. Holomycin, a derivative of thiolutin with reduced toxicity, was also effective at inhibiting NLRP3, paving the way to develop novel agents that selectively target deubiquitination of NLRP3 to regulate its activity.

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