TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation
Tumor necrosis factor receptor-associated factor 6 (TRAF6), the crucial adaptor molecule of receptor activator of NF-κB (RANK), plays an essential role in governing the formation of multi-nucleated osteoclasts. TRAF6 is a RING-dependent ubiquitin (Ub) ligase that in conjunction with Ubc13/Uev1A cata...
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| Veröffentlicht in: | Biochemical and biophysical research communications 2007-08, Vol.359 (4), p.1044-1049 |
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| container_title | Biochemical and biophysical research communications |
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| creator | Lamothe, Betty Webster, William K. Gopinathan, Ambily Besse, Arnaud Campos, Alejandro D. Darnay, Bryant G. |
| description | Tumor necrosis factor receptor-associated factor 6 (TRAF6), the crucial adaptor molecule of receptor activator of NF-κB (RANK), plays an essential role in governing the formation of multi-nucleated osteoclasts. TRAF6 is a RING-dependent ubiquitin (Ub) ligase that in conjunction with Ubc13/Uev1A catalyzes its own auto-ubiquitination via Lys63-linked poly-Ub chains. While the receptor–adaptor function of TRAF6 in RANK signaling is well understood, the significance of its Ub ligase activity in this process remains largely unknown. In this study, we show that retroviral expression of TRAF6, but not a RING mutant of TRAF6 was able to rescue TRAF6-deficient monocytes for the activation of IKK and osteoclast differentiation by RANKL. Furthermore, a catalytically inactive Ubc13 or stable knockdown of Ubc13 significantly prevents RANK-mediated TRAF6 ubiquitination and NF-κB and JNK activation. These data establish a signaling cascade in which regulated Lys63-linked TRAF6 auto-ubiquitination is the critical upstream mediator of osteoclast differentiation. |
| doi_str_mv | 10.1016/j.bbrc.2007.06.017 |
| format | Article |
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TRAF6 is a RING-dependent ubiquitin (Ub) ligase that in conjunction with Ubc13/Uev1A catalyzes its own auto-ubiquitination via Lys63-linked poly-Ub chains. While the receptor–adaptor function of TRAF6 in RANK signaling is well understood, the significance of its Ub ligase activity in this process remains largely unknown. In this study, we show that retroviral expression of TRAF6, but not a RING mutant of TRAF6 was able to rescue TRAF6-deficient monocytes for the activation of IKK and osteoclast differentiation by RANKL. Furthermore, a catalytically inactive Ubc13 or stable knockdown of Ubc13 significantly prevents RANK-mediated TRAF6 ubiquitination and NF-κB and JNK activation. 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TRAF6 is a RING-dependent ubiquitin (Ub) ligase that in conjunction with Ubc13/Uev1A catalyzes its own auto-ubiquitination via Lys63-linked poly-Ub chains. While the receptor–adaptor function of TRAF6 in RANK signaling is well understood, the significance of its Ub ligase activity in this process remains largely unknown. In this study, we show that retroviral expression of TRAF6, but not a RING mutant of TRAF6 was able to rescue TRAF6-deficient monocytes for the activation of IKK and osteoclast differentiation by RANKL. Furthermore, a catalytically inactive Ubc13 or stable knockdown of Ubc13 significantly prevents RANK-mediated TRAF6 ubiquitination and NF-κB and JNK activation. These data establish a signaling cascade in which regulated Lys63-linked TRAF6 auto-ubiquitination is the critical upstream mediator of osteoclast differentiation.</description><subject>Animals</subject><subject>Cell Differentiation - physiology</subject><subject>Cell Line</subject><subject>Humans</subject><subject>Mice</subject><subject>NF-κB</subject><subject>Osteoblasts - cytology</subject><subject>Osteoblasts - metabolism</subject><subject>Osteoclasts</subject><subject>Osteoclasts - cytology</subject><subject>Osteoclasts - metabolism</subject><subject>RANK</subject><subject>RANK Ligand - metabolism</subject><subject>RANKL</subject><subject>RING E3 ubiquitin ligase</subject><subject>Signal Transduction - physiology</subject><subject>TNF Receptor-Associated Factor 6 - metabolism</subject><subject>TRAF6</subject><subject>Ubiquitin-Protein Ligase Complexes - metabolism</subject><issn>0006-291X</issn><issn>1090-2104</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU2LFDEQhoMo7rj6BzxITt66rSTd-QARhmVXxUFhWcVbSNLJmKEn2U26F_z39jiDHxc95VBPvamqB6HnBFoChL_atdYW11IA0QJvgYgHaEVAQUMJdA_RCgB4QxX5eoae1LoDIKTj6jE6I6IXlEm-Ql9urtdXHM823s1xigmPcWuqx7FiX6tPUzQjDrng6_XHDxtc4zaZMaYtNmnAuU4-u9HUCQ8xBF9-8lPM6Sl6FMxY_bPTe44-X13eXLxrNp_evr9YbxrXyW5qpJNEDJw6ZQkTgskgGB0s67w1lBtD--BYsIIJ13vGQ-DKSUa5Jf1gpSLsHL055t7Odu8HtwxQzKhvS9yb8l1nE_XflRS_6W2-13T5CKhcAl6eAkq-m32d9D5W58fRJJ_nqgXwvu8U_S9IlFJU9mIB6RF0JddafPg1DQF98KZ3-uBNH7xp4HrxtjS9-HOP3y0nUQvw-gj45Zr30RddXfTJ-SEW7yY95Piv_B9eF6rD</recordid><startdate>20070810</startdate><enddate>20070810</enddate><creator>Lamothe, Betty</creator><creator>Webster, William K.</creator><creator>Gopinathan, Ambily</creator><creator>Besse, Arnaud</creator><creator>Campos, Alejandro D.</creator><creator>Darnay, Bryant G.</creator><general>Elsevier Inc</general><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>7QP</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20070810</creationdate><title>TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation</title><author>Lamothe, Betty ; Webster, William K. ; Gopinathan, Ambily ; Besse, Arnaud ; Campos, Alejandro D. ; Darnay, Bryant G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c484t-8c817d62c9b137738f732db34eba26aa25fc3fb737c5e36ff69c8326b15db8913</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Cell Differentiation - physiology</topic><topic>Cell Line</topic><topic>Humans</topic><topic>Mice</topic><topic>NF-κB</topic><topic>Osteoblasts - cytology</topic><topic>Osteoblasts - metabolism</topic><topic>Osteoclasts</topic><topic>Osteoclasts - cytology</topic><topic>Osteoclasts - metabolism</topic><topic>RANK</topic><topic>RANK Ligand - metabolism</topic><topic>RANKL</topic><topic>RING E3 ubiquitin ligase</topic><topic>Signal Transduction - physiology</topic><topic>TNF Receptor-Associated Factor 6 - metabolism</topic><topic>TRAF6</topic><topic>Ubiquitin-Protein Ligase Complexes - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lamothe, Betty</creatorcontrib><creatorcontrib>Webster, William K.</creatorcontrib><creatorcontrib>Gopinathan, Ambily</creatorcontrib><creatorcontrib>Besse, Arnaud</creatorcontrib><creatorcontrib>Campos, Alejandro D.</creatorcontrib><creatorcontrib>Darnay, Bryant G.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biochemical and biophysical research communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lamothe, Betty</au><au>Webster, William K.</au><au>Gopinathan, Ambily</au><au>Besse, Arnaud</au><au>Campos, Alejandro D.</au><au>Darnay, Bryant G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation</atitle><jtitle>Biochemical and biophysical research communications</jtitle><addtitle>Biochem Biophys Res Commun</addtitle><date>2007-08-10</date><risdate>2007</risdate><volume>359</volume><issue>4</issue><spage>1044</spage><epage>1049</epage><pages>1044-1049</pages><issn>0006-291X</issn><eissn>1090-2104</eissn><abstract>Tumor necrosis factor receptor-associated factor 6 (TRAF6), the crucial adaptor molecule of receptor activator of NF-κB (RANK), plays an essential role in governing the formation of multi-nucleated osteoclasts. 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| subjects | Animals Cell Differentiation - physiology Cell Line Humans Mice NF-κB Osteoblasts - cytology Osteoblasts - metabolism Osteoclasts Osteoclasts - cytology Osteoclasts - metabolism RANK RANK Ligand - metabolism RANKL RING E3 ubiquitin ligase Signal Transduction - physiology TNF Receptor-Associated Factor 6 - metabolism TRAF6 Ubiquitin-Protein Ligase Complexes - metabolism |
| title | TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation |
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