TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis

TRIM21 is a RING finger domain-containing ubiquitin E3 ligase whose expression is elevated in autoimmune disease. While TRIM21 plays an important role in immune activation during pathogen infection, little is known about its inherent cellular function. Here we show that TRIM21 plays an essential role in redox regulation by directly interacting with SQSTM1/p62 and ubiquitylating p62 at lysine 7 (K7) via K63-linkage. As p62 oligomerizes and sequesters client proteins in inclusions, the TRIM21-mediated p62 ubiquitylation abrogates p62 oligomerization and sequestration of proteins including Keap1, a negative regulator of antioxidant response. TRIM21-deficient cells display an enhanced antioxidant response and reduced cell death in response to oxidative stress. Genetic ablation of TRIM21 in mice confers protection from oxidative damages caused by arsenic-induced liver insult and pressure overload heart injury. Therefore, TRIM21 plays an essential role in p62-regulated redox homeostasis and may be a viable target for treating pathological conditions resulting from oxidative damage. [Display omitted] •SQSTM1/p62 is ubiquitylated by TRIM21 at K7 via K63-linkage•p62 K7 ubiquitylation prevents its dimerization and sequestration•TRIM21 negatively regulates Keap1 sequestration and anti-oxidative response•TRIM21 null liver and heart are protected from oxidative tissue damage Pan et al. show that TRIM21 interacts with and ubiquitylates p62 at K7 via K63-linkage. This p62 K7 ubiquitylation prevents p62 dimerization and sequestration function and negatively regulates the Keap1-Nrf2 redox pathway. TRIM21-null mice are protected from oxidative liver and heart damage.