TRIM25 ubiquitinates and degrades p62/SQSTM1 to suppress autophagy

• TRIM25 is identified as a novel E3 ubiquitin ligase for p62/SQSTM1, promoting its ubiquitination and degradation via autophagy. • The ubiquitination sites K7 and K189 on p62 are critical for TRIM25-mediated degradation, as mutation to arginine abolishes ubiquitination. • TRIM25 knockdown reduces p62 ubiquitination, while exogenous TRIM25 restores it, confirming its role in regulating p62 levels. • The study reveals a mechanism where TRIM25 suppresses autophagy by targeting p62 for autophagic degradation, providing potential therapeutic targets for autophagy-related diseases.