We reveal an unexpected role for ZBTB16 in regulating ASC function. As the linchpin of the multiprotein inflammasome, this regulation of ASC is required for full inflammasome activity. This is underscored by our demonstration that targeting ZBTB16 limits pathogenesis in a mouse model of Muckle-Wells syndrome, which is driven by a hyperactive mutant NLRP3. We show that this control extends to acute inflammatory triggers and identify that this is a cell-intrinsic mechanism of action, thereby ensuring the activity is not due to a general immune impairment41. Experiments with targeted ablation of Zbtb16 and biochemical dissection of the response pathway identify that ZBTB16 promotes ASC SUMOylation. Although several reports have identified the importance of ubiquitination and phosphorylation of inflammasome components, including ASC, there is still little known about the regulation by SUMOylation9–12,42.
