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TRAF6, a Molecular Bridge Spanning Adaptive Immunity, Innate Immunity and Osteoimmunology Hao Wu1* and Joseph R

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TRAF6, a Molecular Bridge Spanning Adaptive Immunity, Innate Immunity and Osteoimmunology Hao Wu1* and Joseph R Review articles TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology Hao Wu1* and Joseph R. Arron2 Summary receptor/Toll-like receptor (IL-1R/TLR) superfamily. Gene Tumor necrosis factor (TNF) receptor associated factor targeting experiments have identified several indispen- 6 (TRAF6) is a crucial signaling molecule regulating a sable physiological functions of TRAF6, and structural diverse array of physiological processes, including and biochemical studies have revealed the potential adaptive immunity, innate immunity, bone metabolism mechanisms of its action. By virtue of its many signaling and the development of several tissues including lymph roles, TRAF6 represents an important target in the regu- nodes, mammary glands, skin and the central nervous lation of many disease processes, including immunity, system. It is a member of a group of six closely related inflammation and osteoporosis. BioEssays 25:1096– TRAF proteins, which serve as adapter molecules, coupl- 1105, 2003. ß 2003 Wiley Periodicals, Inc. ing the TNF receptor (TNFR) superfamily to intracellular signaling events. Among the TRAF proteins, TRAF6 is unique in that, in addition to mediating TNFR family Introduction signaling, it is also essential for signaling downstream of The tumor necrosis factor (TNF) receptor associated factors an unrelated family of receptors, the interleukin-1 (IL-1) (TRAFs) were first identified as two intracellular proteins, TRAF1 and TRAF2, associated with TNF-R2,(1) a member of 1Department of Biochemistry, Weill Medical College of Cornell the TNF receptor (TNFR) superfamily. There are currently six University, New York. mammalian TRAFs (TRAF1-6), which have emerged as 2Tri-Institutional MD-PhD Program, Weill Medical College of Cornell important proximal signal transducers for the TNFR super- University, New York. (2–4) Current affiliation for Dr. Arron: Department of Pathology, Stanford family. In addition, the most recently identified TRAF family University School of Medicine, Stanford, CA member, TRAF6, plays critical roles in the signal transduction Funding agencies: The work was partly supported by NIH (RO1 of the interleukin-1 (IL-1) receptor/Toll-like receptor (IL-1R/ AI45937). H.W. is a Pew Scholar of Biomedical Sciences and a Rita TLR) superfamily.(5,6) By linking the activation of these re- Allen Scholar. J.R.A. is supported by MSTP grant GM-07739 and a ceptors to downstream signaling events, culminating in the Frueauff Foundation Scholarship. *Correspondence to: Hao Wu, Department of Biochemistry, Weill regulation of gene transcription, TRAFs exert indispensable Medical College of Cornell University, 1300 York Avenue, New York, functions in a wide array of physiological and pathological NY 10021. E-mail: [email protected] processes, in particular various aspects of adaptive and innate DOI 10.1002/bies.10352 immunity, inflammation and tissue homeostasis. Published online in Wiley InterScience (www.interscience.wiley.com). Many of the biological effects of TRAF signaling are medi- ated by the activation of kinases such as the IkB kinase (IKK) and mitogen-activated protein (MAP) kinases, which in turn Abbreviations: TNF,tumor necrosis factor; TNFR, TNF receptor; TRAF, modulate the transcriptional activities of the NF-kB and AP-1 TNF receptor associated factor; IL-1, interleukin-1; IL-1R, IL-1 families, respectively. IKK is a hetero-trimeric enzyme com- receptor; TLR, Toll-like receptor; IkB, inhibitor of NF-kB; IKK, IkB prising two kinase subunits, IKKa and IKKb, and a regulatory kinase; MAPK, mitogen-activated protein kinase; MAP2K, MAP kinase subunit, IKKg/NEMO.(7) Upon activation, IKK phosphorylates kinase; MAP3K, MAP kinase kinase kinase; JNK, c-Jun N-terminal kinase; SAPK, stress-activated protein kinase; RANK, receptor the inhibitor of NF-kB, IkB, resulting in its degradation. This activator of NF-kB; TRANCE, TNF-related activation-induced cyto- releases NF-kB, enabling it to translocate to the nucleus and (8) kine; LTbR, lymphotoxin b receptor; LPS, lipopolyssacharides; TIR, activate transcription. MAP kinases are Ser/Thr kinases that Toll/IL-1 receptor domain; MyD88, myeloid differentiation protein 88; include JNKs/SAPKs, ERKs and p38s.(9) They are at the IRAK, IL-1 receptor associated kinase; Mal, MyD88 adapter-like downstream end of a three-tiered system consisting of MAP protein; TIRAP, TIR domain containing adapter protein; EBV, Epstein- Barr virus; HCV, hepatitis C virus; TAK1, transforming growth factor kinase kinases (MAP2Ks) and MAP kinase kinase kinases b-associated kinase 1; TAB1, TAK1-binding protein 1; TAB2, TAK1- (MAP3Ks). Direct phosphorylation and transcriptional activa- binding protein 2. tion of AP-1 components by MAP kinases lead to the stimu- lation of AP-1 activity.(10) While NF-kB is known to promote the 1096 BioEssays 25.11 BioEssays 25:1096–1105, ß 2003 Wiley Periodicals, Inc. Review articles expression of genes involved in inflammatory responses and proteins. TRAFs have been identified in other multicellular protection from apoptosis,(11) the stimulation of AP-1 activity organisms such as Drosophila (dTRAF1-3), Caenorhabditis by MAP kinases may elicit stress responses and promote elegans and Dictyostelium discoideum with a high degree of both cell survival and cell death.(12) evolutionary conservation.(4) TRAFs comprise an N-terminal zinc-binding domain, TRAF-mediated signal transduction is initiated by trimeric specifically a RING finger followed by several zinc fingers, TNF family ligands that induce receptor oligomerization and/or and a C-terminal TRAF domain, consisting of a coiled-coil conformational changes to produce signaling competent domain known as the TRAF-N domain and a highly conserved receptors.(15) This appears to result in the trimerization and TRAF-C domain.(1,13) The N-terminal domain is essential for recruitment of TRAFs through avidity-based affinity enhance- the activation of downstream signaling cascades, and deletion ment,(16) which subsequently activates intracellular signaling of this domain renders it dominant-negative for signaling.(14) pathways. Artificial oligomerization of TRAF2 and TRAF6 has Structural studies have shown that the C-terminal TRAF been shown to activate effector kinases and gene induc- domain adopts a mushroom-like shape with the ‘‘stalk’’ as the tion.(17) Although trimerization per se may be sufficient for coiled-coil TRAF-N domain and the ‘‘head’’ as the TRAF-C signaling by some receptors, it is likely that the formation of domain(13) (Fig. 1a). This TRAF domain permits self-associa- higher-ordered complexes comprising multiple receptor- tion and interactions with receptors and other signaling TRAF trimers localized in one area of the cell membrane upon Figure 1. Structural and sequence analyses of TRAF6. a: Paradigm of TRAF-mediated signal transduction via TRAF trimerization, shown by the symmetrical interaction of trimerized TRAF (cyan, blue and green for the TRAF-C domains and yellow for the coiled coil domains) with receptor peptide (orange arrows). b: Worm Ca traces of superimposed TRAF6 and TRAF2 structures. c: Surface representation of TRAF6, colored based on electrostatic potential (À10kbT/e to 10kbT/e, where kb,Tand e are respectively the Boltzmann constant, temperature and the electron charge), and the bound RANK/TRANCE-R peptide. d: The PxExx(Ar/Ac) TRAF6-binding motif (Ar for aromatic residues; Ac for acidic residues). The surface area buried (SAB) upon TRAF6 interaction for the eight contacting residues (PÀ4 to P3) are shown. CD40 residues that have been mutated to assess their effect on in vitro interaction with TRAF6 are topped with circles (open circle: did not abolish interaction; filled circle: abolished interaction). e: The presence of one or multiple PxExx(Ar/Ac) motifs in RANK/ TRANCE-R, IRAK, IRAK-2, IRAK-M and RIP2. Part of this figure was modified from earlier publications.(4,25) BioEssays 25.11 1097 Review articles ligand engagement may play an essential role and/or enhance cooperate with RIP to directly activate IKK.(30,31) In contrast, signaling for other receptors. the activation of IKK by TRAF6 appears to involve the assembly This review will focus on the biology and signaling mecha- of a large signaling complex containing ubiquitin ligases, TAK1 nism of TRAF6, the most recently discovered mammalian and TABs, for which nondegradative polyubiquitination may be TRAF family member.For general comments on other TRAFs, required.(32,33) The RING domain of TRAF6 is required for this please see recent reviews on the subject.(2–4) signaling event, likely by acting as an E3 ubiquitin ligase. In addition, TRAF6 can also activate Src family nonreceptor TRAF6 is a unique TRAF family member tyrosine kinases such as c-Src,(34) imparting additional TRAF6 was independently cloned by a search against a DNA diversity to TRAF6 signaling. database for TRAF2-like sequences followed by cDNA library screening(18) and by a yeast two-hybrid screen using CD40 Non-redundant role of TRAF6 in the as bait.(19) Unlike other TRAFs, which only mediate signaling signal transduction of members from the TNFR superfamily, TRAF6 also participates in the of the TNFR superfamily signal transduction from the IL-1R/TLR superfamily. The im- The TNFR superfamily is classified based on extensive homo- portance of TRAF6 in signal transduction outside the TNFR logy of extracellular regions containing conserved cysteine- superfamily was first shown by its participation in IL-1 rich repeats.(35) The intracellular regions
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