| Title | TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis. |
| Publication Type | Journal Article |
| Year of Publication | 2016 |
| Authors | Pan J-A, Sun Y, Jiang Y-P, Bott AJ, Jaber N, Dou Z, Yang B, Chen J-S, Catanzaro JM, Du C, Ding W-X, Diaz-Meco MT, Moscat J, Ozato K, Lin RZ, Zong W-X |
| Journal | Mol Cell |
| Volume | 61 |
| Issue | 5 |
| Pagination | 720-733 |
| Date Published | 2016 Mar 03 |
| ISSN | 1097-4164 |
| Keywords | Adaptor Proteins, Signal Transducing, Animals, Arsenic Trioxide, Arsenicals, Cell Death, Chemical and Drug Induced Liver Injury, Cytoskeletal Proteins, Disease Models, Animal, Heart Failure, Heat-Shock Proteins, HEK293 Cells, Homeostasis, Humans, Intracellular Signaling Peptides and Proteins, Kelch-Like ECH-Associated Protein 1, Liver, Lysine, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardium, Oxidation-Reduction, Oxidative Stress, Oxides, Protein Binding, Protein Interaction Domains and Motifs, Protein Multimerization, Ribonucleoproteins, RNA Interference, Sequestosome-1 Protein, Signal Transduction, Time Factors, Transfection, Ubiquitination |
| 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. |
| DOI | 10.1016/j.molcel.2016.02.007 |
| Alternate Journal | Mol Cell |
| PubMed ID | 26942676 |
| PubMed Central ID | PMC4779181 |
| Grant List | R01 DK108743 / DK / NIDDK NIH HHS / United States R01 CA192642 / CA / NCI NIH HHS / United States R01GM97355 / GM / NIGMS NIH HHS / United States P30 CA072720 / CA / NCI NIH HHS / United States R01 GM097355 / GM / NIGMS NIH HHS / United States R01 CA172025 / CA / NCI NIH HHS / United States P30 CA030199 / CA / NCI NIH HHS / United States 5P30CA030199 / CA / NCI NIH HHS / United States R01DK108743 / DK / NIDDK NIH HHS / United States R01CA192642 / CA / NCI NIH HHS / United States R01CA172025 / CA / NCI NIH HHS / United States R01CA129536 / CA / NCI NIH HHS / United States R01 CA129536 / CA / NCI NIH HHS / United States |
Related Faculty:
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.