TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus

• TRIM21 is identified as a novel positive regulator of cGAS-STING signaling in SLE, stabilizing STING by inhibiting its autophagic degradation. • Mechanistically, TRIM21 catalyzes K63-linked polyubiquitylation of p62/SQSTM1, disrupting p62-STING interaction and preventing STING sequestration into autophagosomes. • The TRIM21-p62 axis amplifies type I interferon responses, highlighting a potential therapeutic target for STING-dependent autoimmune disorders. • This study reveals a cross-talk between ubiquitin signaling and autophagy in controlling STING turnover, offering new insights into innate immune regulation.