TRIM21 facilitates inflammasome assembly and contributes to autoinflammatory disease.

Inflammasomes are cytosolic multiprotein complexes facilitating the maturation and release of the inflammatory cytokines interleukin (IL)-1β and IL-18 and pyroptosis. ASC (apoptosis-associated-speck-like protein containing a CARD) is the central inflammasome adaptor. ASC polymerization is crucial for inflammasome assembly, and ASC particle release propagates inflammasome responses to bystander cells. However, control of inflammasome and ASC particle assembly to limit chronic inflammation and the emergence of autoinflammatory diseases is still incompletely understood. Here, we show that the E3 ubiquitin ligase TRIM (tripartite-motif-containing protein) 21, a common autoantigen in autoimmune diseases, is involved in inflammasome assembly. Specifically, TRIM21 binds to and ubiquitinates ASC to facilitate ASC/NLRP3 interactions, ASC polymerization and the release of ASC/TRIM21-containing particles during pyroptosis in human and mouse macrophages. Furthermore, we detect systemic ASC/TRIM21 particles and autoantibodies in human and mouse autoinflammatory disease. Thus, our findings highlight a previously unrecognized role of TRIM21 as an inflammasome component and driver of autoinflammation.