USP46 restrains K63-linked polyubiquitination–dependent aggregation and activation of the NLRP3 inflammasome in lupus nephritis

The activation of the NLRP3 inflammasome necessitates its aggregation within the dispersed trans-Golgi network (dTGN) and subsequent transport from the dTGN to the microtubule organizing center (MTOC), a process facilitated by HDAC6. However, the regulatory mechanisms governing the formation of NLRP3 aggregates remain insufficiently understood. In this study, we demonstrate that proteasome impairment induces polyubiquitination and aggregation of NLRP3 at the MTOC. We demonstrate ubiquitin-specific protease 46 (USP46) as a key factor that recognizes NLRP3 as a substrate and restricts nondegradative K63-linked polyubiquitination at lysine residue K930, thereby preventing excessive aggregation, transport to the MTOC, and inflammasome activation. Furthermore, myeloid-specific knockout of USP46 exacerbates renal injury and inflammation in both lipopolysaccharide-induced-induced endotoxic shock and pristane-induced lupus nephritis models. Our findings provide insights into the regulatory mechanisms underlying the aggresomal activation of the NLRP3 inflammasome.