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

Mol Cell. 2016 Mar 3;61(5):720-733. doi: 10.1016/j.molcel.2016.02.007.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Arsenic Trioxide
  • Arsenicals
  • Cell Death
  • Chemical and Drug Induced Liver Injury / enzymology
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / pathology
  • Chemical and Drug Induced Liver Injury / prevention & control
  • Cytoskeletal Proteins / metabolism
  • Disease Models, Animal
  • HEK293 Cells
  • Heart Failure / enzymology
  • Heart Failure / genetics
  • Heart Failure / pathology
  • Heart Failure / prevention & control
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Homeostasis
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kelch-Like ECH-Associated Protein 1
  • Liver / enzymology
  • Liver / pathology
  • Lysine
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / enzymology
  • Myocardium / pathology
  • Oxidation-Reduction
  • Oxidative Stress*
  • Oxides
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • RNA Interference
  • Ribonucleoproteins / deficiency
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / metabolism*
  • Sequestosome-1 Protein
  • Signal Transduction
  • Time Factors
  • Transfection
  • Ubiquitination*

Substances

  • Adaptor Proteins, Signal Transducing
  • Arsenicals
  • Cytoskeletal Proteins
  • Heat-Shock Proteins
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • Oxides
  • Ribonucleoproteins
  • SQSTM1 protein, human
  • SS-A antigen
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Lysine
  • Arsenic Trioxide