{"id":5234,"date":"2013-06-27T10:51:13","date_gmt":"2013-06-27T01:51:13","guid":{"rendered":"http:\/\/mus.brc.riken.jp:7301\/?page_id=5234"},"modified":"2021-04-07T14:33:36","modified_gmt":"2021-04-07T05:33:36","slug":"sep_2012_mm","status":"publish","type":"page","link":"http:\/\/mus.brc.riken.jp\/ja\/mouse_of_month\/sep_2012_mm","title":{"rendered":"September 2012 Critical roles of TRAF6"},"content":{"rendered":"

\"September<\/a><\/p>\n\n\n\n
\n

<\/h1>\n

Critical roles of TRAF6<\/em><\/h2>\n
\u00a0\u00a0B6;129P2-Traf6tm1Jino<\/sup><\/span>\/JinoRbrc \u00a0\u00a0RBRC04950<\/a><\/h5>\n
C.129P2(B6)-Traf6tm1Jino<\/sup><\/span>\/JinoRbrc \u00a0\u00a0RBRC05386<\/a><\/h5>\n
\"Critical<\/a>
Courtesy of Dr. Jun-ichiro Inoue, The University of Tokyo<\/figcaption><\/figure>\n

Among the live pups examined, only about 12% were Traf6-\/-<\/sup><\/span>, while examination of the embryos revealed a normal Mendelian ratio of Traf6-\/-<\/sup><\/span> mice at day 14.5 post-conception. Viable Traf6-\/-<\/sup><\/span> mice appeared normal at birth, but became smaller than their normal littermates by day 6. Traf6-\/-<\/sup><\/span> mice became more runted with time and died at 17-19 days. Whole body anteroposterior radiographs of 12-day-old Traf6-\/-<\/sup><\/span>mice and their normal littermates revealed that the mutant mice had shortened long bones that were radio-opaque (Fig. 1) and one of their most obvious phenotypes was failure of tooth eruption (Fig. 2). These phenotypes are characteristic of osteopetrosis, a disorder of bone remodeling caused by impaired osteoclast formation or function. In fact, TRAF6 is required for signaling from RANK, an essential receptor for osteoclastogenesis.<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

\n

Tumor necrosis factor (TNF) receptor-associated factor (TRAF) is a cytoplasmic protein that is involved in signaling pathways via the TNF receptor superfamily and the Toll-like receptor\/interleukin-1 (IL-1) receptor superfamily. TRAF6 activates the transcription factors NF-\u03baB and AP-1, and plays essential roles in a variety of biological processes, including osteoclast differentiation, B cell follicle development, lymph node formation, central tolerance of T cells, development and maturation of dendritic cells, development of skin appendices, and survival of neuronal cells [1-14]. Therefore, loss of TRAF6 resulted in various disorders including osteopetrosis, hypohidrotic ectodermal dysplasia, autoimmunity, and a number of problems in both innate and acquired immune responses.<\/p>\n<\/div>\n

\n

In the IL-1R and TLR pathways, IKK activation, an essential process for NF-\u03baB activation, requires the generation of unanchored Lys63-linked polyubiquitin chains or their conjugation to TRAF6 and TGF\u03b2-activated kinase (TAK) 1, both of which are catalyzed by TRAF6 (E3) and the Ubc13\/Uev1A complex (E2). These Lys63-linked polyubiquitin chains act as platforms for the formation of active signal complexes that consist of MEKK3, TAK1, TAK1-binding (TAB) 2\/TAB3, and the IKK complex. Formation of these complexes leads to the activation of TAK1, which then phosphorylates and activates IKK\u03b2 [15]. These knockout mice provide the opportunity to understand the role of TRAF6 in NF-\u03baB activation in various biologically important systems.<\/p>\n<\/div>\n

 <\/p>\n\n\n\n
Depositor<\/td>\n:<\/td>\nDr. Jun-ichiro Inoue<\/strong>
\n Division of Cellular and Molecular Biology, The Institute of Medical Science<\/strong>
\n The University of Tokyo<\/strong><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
References<\/td>\n:<\/td>\n[1]<\/td>\nIshida T, Mizushima S, Azuma S, Kobayashi N, Tojo T, Suzuki K, Aizawa S, Watanabe T, Mosialos G, Kieff E, Yamamoto T, Inoue J<\/span>. Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region. J Biol Chem; 271(46):28745-8, 1996.<\/a><\/td>\n<\/tr>\n
[2]<\/td>\nNaito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K, Nakao K, Nakamura K, Katsuki M, Yamamoto T, Inoue J<\/span>. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells; 4(6):353-62, 1999.<\/a><\/td>\n<\/tr>\n
[3]<\/td>\nKobayashi N, Kadono Y, Naito A, Matsumoto K, Yamamoto T, Tanaka S, Inoue J<\/span>. Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J; 20(6):1271-80, 2001.<\/a><\/td>\n<\/tr>\n
[4]<\/td>\nNaito A, Yoshida H, Nishioka E, Satoh M, Azuma S, Yamamoto T, Nishikawa S, Inoue J<\/span>. TRAF6-deficient mice display hypohidrotic ectodermal dysplasia. Proc Natl Acad Sci U S A; 99(13):8766-71, 2002.<\/a><\/td>\n<\/tr>\n
[5]<\/td>\nYoshida H, Naito A, Inoue J<\/span>, Satoh M, Santee-Cooper SM, Ware CF, Togawa A, Nishikawa S, Nishikawa S. Different cytokines induce surface lymphotoxin-alphabeta on IL-7 receptor-alpha cells that differentially engender lymph nodes and Peyer’s patches. Immunity; 17(6):823-33, 2002.<\/a><\/td>\n<\/tr>\n
[6]<\/td>\nGohda J, Matsumura T, Inoue J<\/span>. Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll\/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling. J Immunol; 173(5):2913-7, 2004.<\/a><\/td>\n<\/tr>\n
[7]<\/td>\nGohda J, Akiyama T, Koga T, Takayanagi H, Tanaka S, Inoue J<\/span>. RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis. EMBO J; 24(4):790-9, 2005.<\/a><\/td>\n<\/tr>\n
[8]<\/td>\nAkiyama T, Maeda S, Yamane S, Ogino K, Kasai M, Kajiura F, Matsumoto M, Inoue J<\/span>. Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science; 308(5719):248-51, 2005.<\/a><\/td>\n<\/tr>\n
[9]<\/td>\nInoue J<\/span>, Gohda J, Akiyama T. Characteristics and Biological Functions of TRAF6. In “TRAFs<\/span>” edited by Hao Wu. Adv Exp Med Biol; 597:72-9, 2007.<\/a><\/td>\n<\/tr>\n
[10]<\/td>\nQin J, Konno H, Ohshima D, Yanai H, Motegi H, Shimo Y, Hirota F, Matsumoto M, Takaki S, Inoue J<\/span>, Akiyama T. Developmental stage-dependentcollaboration between the TNF receptor-associated factor 6 and lymphotoxin pathways for B cell follicle organization in secondary lymphoid organs. J Immunol; 179(10):6799-807, 2007.<\/a><\/td>\n<\/tr>\n
[11]<\/td>\nAkiyama T, Shimo Y, Yanai H, Qin J, Ohshima D, Maruyama Y, Asaumi Y, Kitazawa J, Takayanagi H, Penninger JM, Matsumoto M, Nitta T, Takahama Y, Inoue J<\/span>. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity; 29(3):423-37, 2008.<\/a><\/td>\n<\/tr>\n
[12]<\/td>\nKonno H, Yamamoto T, Yamazaki K, Gohda J, Akiyama T, Semba K, Goto H, Kato A, Yujiri T, Imai T, Kawaguchi Y, Su B, Takeuchi O, Akira S, Tsunetsugu-Yokota Y, Inoue J<\/span>. TRAF6 establishes innate immune responses by activating NF-kappaB and IRF7 upon sensing cytosolic viral RNA and DNA. PLoS One; 4(5):e5674, 2009.<\/a><\/td>\n<\/tr>\n
[13]<\/td>\nMotegi H, Shimo Y, Akiyama T, Inoue J<\/span>. TRAF6 negatively regulates the Jak1-Erk pathway in interleukin-2 signaling. Genes Cells; 16(2):179-89, 2011.<\/a><\/td>\n<\/tr>\n
[14]<\/td>\nShimo Y, Yanai H, Ohshima D, Qin J, Motegi H, Maruyama Y, Hori S, Inoue J<\/span>, Akiyama T. TRAF6 directs commitment to regulatory T cells in thymocytes. Genes Cells; 16(4):437-47, 2011.<\/a><\/td>\n<\/tr>\n
[15]<\/td>\nYamazaki K, Gohda J, Kanayama A, Miyamoto Y, Sakurai H, Yamamoto M, Akira S, Hayashi H, Su B, Inoue J<\/span>. Two mechanistically and temporally distinct NF-kappaB activation pathways in IL-1 signaling. Sci Signal; 2(93):ra66, 2009.<\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

Critical roles of TRAF6 \u00a0\u00a0B6;129P2-Traf6tm1Jino\/JinoRbrc \u00a0\u00a0RBRC04950 C.129P2(B6)-Traf6tm1Jino\/JinoRbrc \u00a0\u00a0RBRC05386 Among the live pups examined, only about 12% were Traf6-\/-, while examination of the […]<\/p>\n","protected":false},"author":8,"featured_media":0,"parent":198,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","_seopress_robots_follow":"","_seopress_robots_imageindex":"","_seopress_robots_snippet":"","_seopress_robots_primary_cat":"","_seopress_robots_breadcrumbs":"","_seopress_robots_freeze_modified_date":"","_seopress_robots_custom_modified_date":"","_seopress_robots_canonical":"","_seopress_social_fb_title":"","_seopress_social_fb_desc":"","_seopress_social_fb_img":"","_seopress_social_fb_img_attachment_id":0,"_seopress_social_fb_img_width":0,"_seopress_social_fb_img_height":0,"_seopress_social_twitter_title":"","_seopress_social_twitter_desc":"","_seopress_social_twitter_img":"","_seopress_social_twitter_img_attachment_id":0,"_seopress_social_twitter_img_width":0,"_seopress_social_twitter_img_height":0,"_seopress_redirections_value":"","_seopress_redirections_enabled":"","_seopress_redirections_enabled_regex":"","_seopress_redirections_logged_status":"","_seopress_redirections_param":"","_seopress_redirections_type":301,"_seopress_analysis_target_kw":"","footnotes":"","_wp_rev_ctl_limit":""},"class_list":["post-5234","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"http:\/\/mus.brc.riken.jp\/ja\/wp-json\/wp\/v2\/pages\/5234","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/mus.brc.riken.jp\/ja\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"http:\/\/mus.brc.riken.jp\/ja\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"http:\/\/mus.brc.riken.jp\/ja\/wp-json\/wp\/v2\/users\/8"}],"replies":[{"embeddable":true,"href":"http:\/\/mus.brc.riken.jp\/ja\/wp-json\/wp\/v2\/comments?post=5234"}],"version-history":[{"count":13,"href":"http:\/\/mus.brc.riken.jp\/ja\/wp-json\/wp\/v2\/pages\/5234\/revisions"}],"predecessor-version":[{"id":18187,"href":"http:\/\/mus.brc.riken.jp\/ja\/wp-json\/wp\/v2\/pages\/5234\/revisions\/18187"}],"up":[{"embeddable":true,"href":"http:\/\/mus.brc.riken.jp\/ja\/wp-json\/wp\/v2\/pages\/198"}],"wp:attachment":[{"href":"http:\/\/mus.brc.riken.jp\/ja\/wp-json\/wp\/v2\/media?parent=5234"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}