title: TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis.
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.
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Molecular Genetics & Microbiology, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: jian.pan@pharmacy.rutgers.edu.
authors.forename: Ji-An
authors.initials: JA
authors.lastname: Pan
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Molecular Genetics & Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Jiang
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Molecular Genetics & Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Bott
authors.affiliation: Department of Molecular Genetics & Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Jaber
authors.affiliation: Department of Molecular Genetics & Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Zhixun
authors.initials: Z
authors.lastname: Dou
authors.affiliation: Key Laboratory of Artificial Cells, Tianjin Third Central Hospital, Tianjin 300170, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Molecular Genetics & Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Juei-Suei
authors.initials: JS
authors.lastname: Chen
authors.affiliation: Department of Molecular Genetics & Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Catanzaro
authors.affiliation: Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Du
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Ding
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.affiliation: Division of Developmental Biology, NICHD, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA; Department of Veterans Affairs Medical Center, Northport, NY 11768, USA.
authors.forename: Richard Z
authors.initials: RZ
authors.lastname: Lin
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Molecular Genetics & Microbiology, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: weixing.zong@pharmacy.rutgers.edu.
authors.forename: Wei-Xing
authors.initials: WX
authors.lastname: Zong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals; D016923:Cell Death; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008239:Lysine; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010087:Oxides; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D034622:RNA Interference; D012261:Ribonucleoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination; D000099207:SS-A Antigen
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000077237:Arsenic Trioxide; D001152:Arsenicals; D003598:Cytoskeletal Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D008239:Lysine; D010087:Oxides; D012261:Ribonucleoproteins; D000071456:Sequestosome-1 Protein; D000099207:SS-A Antigen; C431364:KEAP1 protein, human; C117301:Keap1 protein, mouse; C099718:SQSTM1 protein, human; C101343:Sqstm1 protein, mouse