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

TitleTRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis.
Publication TypeJournal Article
Year of Publication2016
AuthorsPan 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
JournalMol Cell
Volume61
Issue5
Pagination720-733
Date Published2016 Mar 03
ISSN1097-4164
KeywordsAdaptor 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.

DOI10.1016/j.molcel.2016.02.007
Alternate JournalMol Cell
PubMed ID26942676
PubMed Central IDPMC4779181
Grant ListR01 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.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700