Critical roles of TRAF6
Among the live pups examined, only about 12% were Traf6-/-, while examination of the embryos revealed a normal Mendelian ratio of Traf6-/- mice at day 14.5 post-conception. Viable Traf6-/- mice appeared normal at birth, but became smaller than their normal littermates by day 6. Traf6-/- mice became more runted with time and died at 17-19 days. Whole body anteroposterior radiographs of 12-day-old Traf6-/-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.
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-κB 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.
In the IL-1R and TLR pathways, IKK activation, an essential process for NF-κB activation, requires the generation of unanchored Lys63-linked polyubiquitin chains or their conjugation to TRAF6 and TGFβ-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 IKKβ . These knockout mice provide the opportunity to understand the role of TRAF6 in NF-κB activation in various biologically important systems.
|Depositor||:||Dr. Jun-ichiro Inoue
Division of Cellular and Molecular Biology, The Institute of Medical Science
The University of Tokyo
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