TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology Hao Wu 1 * and Joseph R. Arron 2 Summary 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, coupl- 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 signaling, it is also essential for signaling downstream of an unrelated family of receptors, the interleukin-1 (IL-1) receptor/Toll-like receptor (IL-1R/TLR) superfamily. Gene targeting experiments have identified several indispen- sable physiological functions of TRAF6, and structural and biochemical studies have revealed the potential mechanisms of its action. By virtue of its many signaling roles, TRAF6 represents an important target in the regu- lation of many disease processes, including immunity, inflammation and osteoporosis. BioEssays 25:1096– 1105, 2003. ß 2003 Wiley Periodicals, Inc. Introduction The tumor necrosis factor (TNF) receptor associated factors (TRAFs) were first identified as two intracellular proteins, TRAF1 and TRAF2, associated with TNF-R2, (1) a member of the TNF receptor (TNFR) superfamily. There are currently six mammalian TRAFs (TRAF1-6), which have emerged as important proximal signal transducers for the TNFR super- family. (2–4) In addition, the most recently identified TRAF family member, TRAF6, plays critical roles in the signal transduction of the interleukin-1 (IL-1) receptor/Toll-like receptor (IL-1R/ TLR) superfamily. (5,6) By linking the activation of these re- ceptors to downstream signaling events, culminating in the regulation of gene transcription, TRAFs exert indispensable functions in a wide array of physiological and pathological processes, in particular various aspects of adaptive and innate immunity, inflammation and tissue homeostasis. 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 modulate the transcriptional activities of the NF-kB and AP-1 families, respectively. IKK is a hetero-trimeric enzyme com- prising two kinase subunits, IKKa and IKKb, and a regulatory subunit, IKKg/NEMO. (7) Upon activation, IKK phosphorylates the inhibitor of NF-kB, IkB, resulting in its degradation. This releases NF-kB, enabling it to translocate to the nucleus and activate transcription. (8) MAP kinases are Ser/Thr kinases that include JNKs/SAPKs, ERKs and p38s. (9) They are at the downstream end of a three-tiered system consisting of MAP kinase kinases (MAP2Ks) and MAP kinase kinase kinases (MAP3Ks). Direct phosphorylation and transcriptional activa- 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. 1 Department of Biochemistry, Weill Medical College of Cornell University, New York. 2 Tri-Institutional MD-PhD Program, Weill Medical College of Cornell University, New York. Current affiliation for Dr. Arron: Department of Pathology, Stanford University School of Medicine, Stanford, CA Funding agencies: The work was partly supported by NIH (RO1 AI45937). H.W. is a Pew Scholar of Biomedical Sciences and a Rita Allen Scholar. J.R.A. is supported by MSTP grant GM-07739 and a Frueauff Foundation Scholarship. *Correspondence to: Hao Wu, Department of Biochemistry, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021. E-mail: haowu@med.cornell.edu DOI 10.1002/bies.10352 Published online in Wiley InterScience (www.interscience.wiley.com). Abbreviations: TNF, tumor necrosis factor; TNFR, TNFreceptor; TRAF, TNF receptor associated factor; IL-1, interleukin-1; IL-1R, IL-1 receptor; TLR, Toll-like receptor; IkB, inhibitor of NF-kB; IKK, IkB kinase; MAPK, mitogen-activated protein kinase; MAP2K, MAP kinase kinase; MAP3K, MAP kinase kinase kinase; JNK, c-Jun N-terminal kinase; SAPK, stress-activated protein kinase; RANK, receptor activator of NF-kB; TRANCE, TNF-related activation-induced cyto- kine; LTbR, lymphotoxin b receptor; LPS, lipopolyssacharides; TIR, Toll/IL-1 receptor domain; MyD88, myeloid differentiation protein 88; IRAK, IL-1 receptor associated kinase; Mal, MyD88 adapter-like protein; TIRAP, TIR domain containing adapter protein; EBV, Epstein- Barr virus; HCV, hepatitis C virus; TAK1, transforming growth factor b-associated kinase 1; TAB1, TAK1-binding protein 1; TAB2, TAK1- binding protein 2. Review articles