TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology

  title={TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology},
  author={Hao Wu and Joseph R. Arron},
Tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) is a crucial signaling molecule regulating a diverse array of physiological processes, including adaptive immunity, innate immunity, bone metabolism and the development of several tissues including lymph nodes, mammary glands, skin and the central nervous system. It is a member of a group of six closely related TRAF proteins, which serve as adapter molecules, coupling the TNF receptor (TNFR) superfamily to intracellular signaling… 
Mechanism by which TRAF6 Participates in the Immune Regulation of Autoimmune Diseases and Cancer
The role of TRAf6 in certain immune cells, as well as the function and potential effect of TRAF6 in autoimmune diseases and cancer, are reviewed and indicates that TRAF 6 may be a novel target for autoimmune Diseases and cancer.
TRAF Molecules in Inflammation and Inflammatory Diseases
Increasing evidence indicates that TRAF molecules are versatile and indispensable regulators of inflammation and inflammatory responses and that aberrant expression or function of TRAFs contributes to the pathogenesis of inflammatory diseases.
Assembly of post-receptor signaling complexes for the tumor necrosis factor receptor superfamily.
  • Hao Wu
  • Biology, Chemistry
    Advances in protein chemistry
  • 2004
TRAFs in RANK signaling.
Evidence from various research laboratories indicates TRAFs, but more importantly TRAF6, is the key to understanding how RANKL links cytoplasmic signaling to the nuclear transcriptional program.
Keratin 8 limits TLR-triggered inflammatory responses through inhibiting TRAF6 polyubiquitination
It is reported that down-regulation of CK8 in mice enhanced TLR-mediated responses, rendering mice more susceptible to lipopolysaccharide (LPS)-induced endotoxin shock and Escherichia coli–caused septic peritonitis with reduced survival, elevated levels of inflammation cytokines and more severe tissue damage.
Increased A20-E3 ubiquitin ligase interactions in bid-deficient glia attenuate TLR3- and TLR4-induced inflammation
This study demonstrates that Bid promotes E3 ubiquitin ligase-mediated signaling downstream of TLR3 and TLR4 and provides further evidence for the potential of Bid inhibition as a therapeutic for the attenuation of the robust pro-inflammatory response culminating in TLR activation.
TRAF6 deficiency promotes TNF-induced cell death through inactivation of GSK3β
A role for TRAF6 is suggested in the maintenance of cell survival by regulating GSK3β activity in TNF signaling by regulating TNF-induced p65/RelA phosphorylation and inactivation of glycogen synthase kinase 3β.
The relationship between TRAF6 and tumors
Tumor necrosis factor receptor-associated factor 6 (TRAF6) is upregulated in various tumors, which has been related to tumorigenesis and development.
TRAF6 regulates proliferation and differentiation of skeletal myoblasts.


Distinct molecular mechanism for initiating TRAF6 signalling
Crystal structures of TRAF6 are reported to identify a universal mechanism by which TRAF 6 regulates several signalling cascades in adaptive immunity, innate immunity and bone homeostasis.
TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling.
It is reported that mice deficient in TNF receptor-associated factor 6 (TRAF6) are osteopetrotic with defects in bone remodeling and tooth eruption due to impaired osteoclast function, and it is demonstrated that TRAF6 is crucial not only in IL-1 and CD40 signaling but also, surprisingly, in LPS signaling.
Segregation of TRAF6‐mediated signaling pathways clarifies its role in osteoclastogenesis
TRAF6 plays essential roles in both the differentiation and maturation of osteoclasts by activating various kinases via its multiple domains under physiological conditions established by appropriate expression of TRAF6 mutants in TRAF 6‐deficient cells.
Thermodynamic characterization of the interaction between TRAF2 and tumor necrosis factor receptor peptides by isothermal titration calorimetry.
  • H. Ye, H. Wu
  • Chemistry, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2000
The tumor necrosis factor receptor (TNFR) superfamily can induce diverse biological effects, including cell survival, proliferation, differentiation, and apoptosis. The major signal transducers for
Anatomy of TRAF2
Examination of point mutants and TRAF2-TRAF3 chimeric proteins indicates that the N-terminal RING finger and two adjacent zinc fingers of TRAf2 are required for NF-κB activation, and distinct domains of TRAF 2 are involved in recruitment and signaling functions.
Requirement of Tumor Necrosis Factor Receptor–Associated Factor (Traf)6 in Interleukin 17 Signal Transduction
The requirement of tumor necrosis factor receptor–associated factor (TRAF)6 in IL-17–induced NF-κB and JNK activation is reported, indicating that TRAF6, but not TRAF2, is a crucial component in the IL- 17 signaling pathway leading to proinflammatory responses.
RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase.
A novel 61-kDa protein kinase related to RIP is identified and characterized that is a component of both the TNFR-1 and the CD40 signaling complexes and reveals the pro-apoptotic function of RIP2 to be restricted to its C-terminal CARD domain, whereas the intact molecule was necessary for NF-kappaB activation.
Membrane Localization of TRAF 3 Enables JNK Activation*
It is shown that, among the known TRAFs, localization to the insoluble cell pellet fraction consistently correlates with JNK activation and that both characteristics map to the TRAF N terminus, and it is demonstrated that forced localization of TRAF 3 to the cell membrane is sufficient to convert this molecule into an activator of JNK.
Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family.
Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4
It is shown by gene-targeting that IRAK-4, an IRAK molecule closely related to the Drosophila Pelle protein, is indispensable for the responses of animals and cultured cells to IL-1 and ligands that stimulate various TLRs.