Here we identify a molecular mechanism that controls the central adaptor molecule ASC. Our study identifies that ZBTB16 interacts with ASC, UBC9 and SUMO via its BTB/POZ and RD2 domains. This is shown to facilitate the modification of ASC with one of the three SUMO paralogs, SUMO116. The specific residues on ASC that control its SUMOylation are identified and we demonstrate that the ZBTB16-dependent modification of ASC with SUMO1 in the nucleus promotes the assembly of the inflammasome complex in the cytosol. This deciphers an important molecular mechanism of inflammasome assembly. The impact of this mechanism is tested in cell lines and in vivo with specific inflammatory stimuli using constitutive and targeted Zbtb16 mutant animals as well as a mouse model of Muckle-Wells syndrome that has a hyperactive inflammasome. Together these data identify a ZBTB16-SUMO1-ASC axis that promotes inflammasome activity with consequences for inflammatory immunity.
