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

USP46 restrains K63-linked polyubiquitination at NLRP3 lysine K930, limiting NLRP3 aggregation, MTOC transport, and inflammasome activation in lupus nephritis models.

• Why it matters: NLRP3 activation depends on aggresome-like aggregation and trafficking, but how these aggregate formation steps are regulated is unclear, especially in inflammatory kidney disease.
• What they did: The study shows proteasome impairment triggers K63-linked polyubiquitination and NLRP3 aggregation at the MTOC, and identifies USP46 as a substrate-recognizing factor that restricts nondegradative ubiquitination at K930.
• The result: Myeloid-specific USP46 knockout worsens renal injury and inflammation in lipopolysaccharide-induced endotoxic shock and pristane-induced lupus nephritis, implying USP46 limits pathogenic NLRP3 aggresomal activation.

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