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 rol...
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| Veröffentlicht in: | Molecular cell 2016-03, Vol.61 (5), p.720-733 |
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| creator | Pan, Ji-An Sun, Yu Jiang, Ya-Ping Bott, Alex J. Jaber, Nadia Dou, Zhixun Yang, Bin Chen, Juei-Suei Catanzaro, Joseph M. Du, Chunying Ding, Wen-Xing Diaz-Meco, Maria T. Moscat, Jorge Ozato, Keiko Lin, Richard Z. Zong, Wei-Xing |
| description | 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. |
| doi_str_mv | 10.1016/j.molcel.2016.02.007 |
| format | Article |
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[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.</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/j.molcel.2016.02.007</identifier><identifier>PMID: 26942676</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>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 ; Heart Failure - enzymology ; Heart Failure - genetics ; Heart Failure - pathology ; Heart Failure - prevention & control ; Heat-Shock Proteins - genetics ; Heat-Shock Proteins - metabolism ; HEK293 Cells ; 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 ; Ribonucleoproteins - deficiency ; Ribonucleoproteins - genetics ; Ribonucleoproteins - metabolism ; RNA Interference ; Sequestosome-1 Protein ; Signal Transduction ; Time Factors ; Transfection ; Ubiquitination</subject><ispartof>Molecular cell, 2016-03, Vol.61 (5), p.720-733</ispartof><rights>2016 Elsevier Inc.</rights><rights>Copyright © 2016 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-dc25d74f7773495bdecbc2932155c5b6900861f3e1de7b497151ea919a5763ac3</citedby><cites>FETCH-LOGICAL-c463t-dc25d74f7773495bdecbc2932155c5b6900861f3e1de7b497151ea919a5763ac3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.molcel.2016.02.007$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,315,781,785,886,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26942676$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pan, Ji-An</creatorcontrib><creatorcontrib>Sun, Yu</creatorcontrib><creatorcontrib>Jiang, Ya-Ping</creatorcontrib><creatorcontrib>Bott, Alex J.</creatorcontrib><creatorcontrib>Jaber, Nadia</creatorcontrib><creatorcontrib>Dou, Zhixun</creatorcontrib><creatorcontrib>Yang, Bin</creatorcontrib><creatorcontrib>Chen, Juei-Suei</creatorcontrib><creatorcontrib>Catanzaro, Joseph M.</creatorcontrib><creatorcontrib>Du, Chunying</creatorcontrib><creatorcontrib>Ding, Wen-Xing</creatorcontrib><creatorcontrib>Diaz-Meco, Maria T.</creatorcontrib><creatorcontrib>Moscat, Jorge</creatorcontrib><creatorcontrib>Ozato, Keiko</creatorcontrib><creatorcontrib>Lin, Richard Z.</creatorcontrib><creatorcontrib>Zong, Wei-Xing</creatorcontrib><title>TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>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.</description><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Animals</subject><subject>Arsenic Trioxide</subject><subject>Arsenicals</subject><subject>Cell Death</subject><subject>Chemical and Drug Induced Liver Injury - enzymology</subject><subject>Chemical and Drug Induced Liver Injury - genetics</subject><subject>Chemical and Drug Induced Liver Injury - pathology</subject><subject>Chemical and Drug Induced Liver Injury - prevention & control</subject><subject>Cytoskeletal Proteins - metabolism</subject><subject>Disease Models, Animal</subject><subject>Heart Failure - enzymology</subject><subject>Heart Failure - genetics</subject><subject>Heart Failure - pathology</subject><subject>Heart Failure - prevention & control</subject><subject>Heat-Shock Proteins - genetics</subject><subject>Heat-Shock Proteins - metabolism</subject><subject>HEK293 Cells</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Kelch-Like ECH-Associated Protein 1</subject><subject>Liver - enzymology</subject><subject>Liver - pathology</subject><subject>Lysine</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Myocardium - enzymology</subject><subject>Myocardium - pathology</subject><subject>Oxidation-Reduction</subject><subject>Oxidative Stress</subject><subject>Oxides</subject><subject>Protein Binding</subject><subject>Protein Interaction Domains and Motifs</subject><subject>Protein Multimerization</subject><subject>Ribonucleoproteins - deficiency</subject><subject>Ribonucleoproteins - genetics</subject><subject>Ribonucleoproteins - metabolism</subject><subject>RNA Interference</subject><subject>Sequestosome-1 Protein</subject><subject>Signal Transduction</subject><subject>Time Factors</subject><subject>Transfection</subject><subject>Ubiquitination</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1OHDEQhS2UiL9wgyjqC0zjcvtnvIkUoRCQQEmYYW257RriUU-7sd0o3CZnycno0QBJNllVlUrv1auPkPdAa6AgT9f1JnYOu5pNU01ZTanaI4dAtZpxkPzNc8-UFAfkKOc1pcDFXO-TAyY1Z1LJQ-KWN5fXDH7_um3D_RjKY2cL5mrxfbG8htNBssr2vlqMw5Aw52nzLcWCoa8WeD9iLsmWEPuqxOoG78ateGp8_FldxA3GXGwO-R15u7JdxpPnekxuzz8vzy5mV1-_XJ59upo5Lpsy844Jr_hKKdVwLVqPrnVMNwyEcKKVmtK5hFWD4FG1XCsQgFaDtkLJxrrmmHzc-Q5ju0HvsJ_idWZIYWPTo4k2mH83ffhh7uKD4UppmMNkwHcGLsWcE65etUDNFrpZmx10s4VuKDMT9En24e-7r6IXyn-C4fT9Q8BksgvYO_QhoSvGx_D_C08pZpd_</recordid><startdate>20160303</startdate><enddate>20160303</enddate><creator>Pan, Ji-An</creator><creator>Sun, Yu</creator><creator>Jiang, Ya-Ping</creator><creator>Bott, Alex J.</creator><creator>Jaber, Nadia</creator><creator>Dou, Zhixun</creator><creator>Yang, Bin</creator><creator>Chen, Juei-Suei</creator><creator>Catanzaro, Joseph M.</creator><creator>Du, Chunying</creator><creator>Ding, Wen-Xing</creator><creator>Diaz-Meco, Maria T.</creator><creator>Moscat, Jorge</creator><creator>Ozato, Keiko</creator><creator>Lin, Richard Z.</creator><creator>Zong, Wei-Xing</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20160303</creationdate><title>TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis</title><author>Pan, Ji-An ; Sun, Yu ; Jiang, Ya-Ping ; Bott, Alex J. ; Jaber, Nadia ; Dou, Zhixun ; Yang, Bin ; Chen, Juei-Suei ; Catanzaro, Joseph M. ; Du, Chunying ; Ding, Wen-Xing ; Diaz-Meco, Maria T. ; Moscat, Jorge ; Ozato, Keiko ; Lin, Richard Z. ; Zong, Wei-Xing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-dc25d74f7773495bdecbc2932155c5b6900861f3e1de7b497151ea919a5763ac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Animals</topic><topic>Arsenic Trioxide</topic><topic>Arsenicals</topic><topic>Cell Death</topic><topic>Chemical and Drug Induced Liver Injury - enzymology</topic><topic>Chemical and Drug Induced Liver Injury - genetics</topic><topic>Chemical and Drug Induced Liver Injury - pathology</topic><topic>Chemical and Drug Induced Liver Injury - prevention & control</topic><topic>Cytoskeletal Proteins - metabolism</topic><topic>Disease Models, Animal</topic><topic>Heart Failure - enzymology</topic><topic>Heart Failure - genetics</topic><topic>Heart Failure - pathology</topic><topic>Heart Failure - prevention & control</topic><topic>Heat-Shock Proteins - genetics</topic><topic>Heat-Shock Proteins - metabolism</topic><topic>HEK293 Cells</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Kelch-Like ECH-Associated Protein 1</topic><topic>Liver - enzymology</topic><topic>Liver - pathology</topic><topic>Lysine</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Myocardium - enzymology</topic><topic>Myocardium - pathology</topic><topic>Oxidation-Reduction</topic><topic>Oxidative Stress</topic><topic>Oxides</topic><topic>Protein Binding</topic><topic>Protein Interaction Domains and Motifs</topic><topic>Protein Multimerization</topic><topic>Ribonucleoproteins - deficiency</topic><topic>Ribonucleoproteins - genetics</topic><topic>Ribonucleoproteins - metabolism</topic><topic>RNA Interference</topic><topic>Sequestosome-1 Protein</topic><topic>Signal Transduction</topic><topic>Time Factors</topic><topic>Transfection</topic><topic>Ubiquitination</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pan, Ji-An</creatorcontrib><creatorcontrib>Sun, Yu</creatorcontrib><creatorcontrib>Jiang, Ya-Ping</creatorcontrib><creatorcontrib>Bott, Alex J.</creatorcontrib><creatorcontrib>Jaber, Nadia</creatorcontrib><creatorcontrib>Dou, Zhixun</creatorcontrib><creatorcontrib>Yang, Bin</creatorcontrib><creatorcontrib>Chen, Juei-Suei</creatorcontrib><creatorcontrib>Catanzaro, Joseph M.</creatorcontrib><creatorcontrib>Du, Chunying</creatorcontrib><creatorcontrib>Ding, Wen-Xing</creatorcontrib><creatorcontrib>Diaz-Meco, Maria T.</creatorcontrib><creatorcontrib>Moscat, Jorge</creatorcontrib><creatorcontrib>Ozato, Keiko</creatorcontrib><creatorcontrib>Lin, Richard Z.</creatorcontrib><creatorcontrib>Zong, Wei-Xing</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pan, Ji-An</au><au>Sun, Yu</au><au>Jiang, Ya-Ping</au><au>Bott, Alex J.</au><au>Jaber, Nadia</au><au>Dou, Zhixun</au><au>Yang, Bin</au><au>Chen, Juei-Suei</au><au>Catanzaro, Joseph M.</au><au>Du, Chunying</au><au>Ding, Wen-Xing</au><au>Diaz-Meco, Maria T.</au><au>Moscat, Jorge</au><au>Ozato, Keiko</au><au>Lin, Richard Z.</au><au>Zong, Wei-Xing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2016-03-03</date><risdate>2016</risdate><volume>61</volume><issue>5</issue><spage>720</spage><epage>733</epage><pages>720-733</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><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.
[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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>26942676</pmid><doi>10.1016/j.molcel.2016.02.007</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 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 Heart Failure - enzymology Heart Failure - genetics Heart Failure - pathology Heart Failure - prevention & control Heat-Shock Proteins - genetics Heat-Shock Proteins - metabolism HEK293 Cells 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 Ribonucleoproteins - deficiency Ribonucleoproteins - genetics Ribonucleoproteins - metabolism RNA Interference Sequestosome-1 Protein Signal Transduction Time Factors Transfection Ubiquitination |
| title | TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis |
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