TRAF Pathway

The structural and metabolic integrity of bone is maintained through the dynamic process of bone remodeling that results from the coordinate action of bone resorption and the formation of new bone by osteoblasts. Regulation of bone remodeling occurs through multiple mechanisms that ultimately converge on the interaction of osteoclasts or their precursors with osteoblasts and bone marrow stromal cells. Two key factors supplied by the stromal environment are CSF1 (Colony-Stimulating Factor-1) and the TNF family member, RANKL (Receptor Activator of Nuclear Factor-κB Ligand, also called TRANCE, ODF, OPGL). Signaling through RANK is essential for the differentiation and activation of osteoclasts, the cell principally responsible for bone resorption. RANK provokes biochemical signaling via the recruitment of intracellular adaptor TRAFs (TNF [Tumor Necrosis Factor] Receptor-Associated Factors) after ligand binding and receptor oligomerization (Ref.1).

TRAFs represent a group of structurally similar adaptor proteins characterized by having RING finger domains, multiple Zn2+ fingers, and a conserved COOH-terminal TD (TRAF Domain) (Ref.2). TRAFs function as molecular bridges, linking the cytosolic portions of the receptors to downstream protein kinases, ubiquitin ligases, and other adaptor proteins. To date, six TRAF family proteins (TRAF1-6) have been identified, and all mediate signal transduction by one or more members of the TNFR family. TRAF proteins are recruited to cell surface receptors indirectly through other intracellular proteins. TRAF1 is found almost exclusively in activated lymphocytes, dendritic cells, and certain epithelia and is unique among TRAFs because it contains only one Zn2+ finger and lacks the RING domain found near the NH2-terminal regions of TRAF2-6. The RING domain is critical for the activation of NF-κB or JNK (c-Jun N-terminal Kinase) (Ref.3). TRAF4 is also distinct from other TRAFs in that it possesses nuclear localization signals (Ref.4). TRAF2 binds TRADD (TNFR-Associated Death Domain), which interacts with TNFR1. TRAF6 interacts with IL-1R (Interleukin-1 Receptor)-associated kinase, which is recruited to the TLR (Toll/IL-1R like Receptor) complexes through MyD88. Once recruited, MyD88 interacts with 2 IRAK (IL-1 Receptor-Associated Kinases), IRAK1 and IRAK2, which are pre-associated with the regulatory protein TollIP (Toll-Interacting Protein). Phosphorylated IRAK dissociates from MyD88, and associates with TRAF6, which is preassembled in a complex with TAK1 (TGF-β-Activating Kinase-1) binding proteins TAB1 and TAB2 (TAK1 Binding Protein). TRAF6 triggers the phosphorylation and activation of TAK1 in an ubiquitination-dependent manner. TAK1 then activate two kinase cascades (Ref.5), one leads to the activation of JNK, and the other cascade leads to the activation of the IKK (I-κB Kinases), which phosphorylate I-κB (Inhibitor of κ Light Chain Gene Enhancer in B-Cells). This phosphorylation triggers ubiquitination and subsequent degradation of IκB, resulting in the release of NF-κB subunits that translocate to the nucleus, where they induce the transcriptional activation of a wide variety of inflammatory and immune response genes (Ref.6).

TNFR1 recruits a TRADD-dependent complex containing TRAF1, TRAF2, cIAP1 and cIAP2 (Inhibitor of Apoptosis), which bind FADD (Fas-Associated Death Domain), a cysteine aspartase, Caspase8 binding protein, and suppress Caspase8 activation, thereby preventing apoptosis through Caspase cascades (Caspase3, 6 and 7). Alternatively, recruitment of TRAF1 to some TNFR family members suppress apoptosis indirectly by enhancing (rather than suppressing) NF-κB activation, whereby NF-κB then directly induce the transcription of several antiapoptotic proteins including cIAP1, cIAP2 (and possibly other IAPs), FLICE (FADD-Like IL-1β Converting Enzyme)-like inhibitory protein FLIP, and BCL2 (B-Cell Lymphomal Leukemia) members: BCLXL and Bfl1. RIP (Receptor-Interacting Protein) binds TRAF2 on TNFR2 and recruits TRADD, which binds FADD and triggers apoptosis by activating Caspase8. If RIP is absent, then TRAF2 activates NF-κB and apoptosis is avoided (Ref.3). In addition, the death domain kinase RIP and the serine-threonine kinase IRAK (IL-1 receptor-associated kinases) also interact with TRAF proteins and mediate NF-κB and activation of certain Activating Proteins. On the other hand, a TRAF interacting kinase, ASK1 (Apoptosis Signal-Regulating Kinase), act as a downstream target of TRAF2, TRAF5, and TRAF6 in the JNK/SAPK (Stress-Activated Protein Kinase) and p38 MAPK signaling pathway (Ref.2). For the activation of JNK, other serine/threonine kinases MAP3K and MAP4K, GCK (Germinal Center Kinase) and GCKR (GCK Receptor), MEKK1 (MAPK/ERK-regulated kinase kinase-1), TAK1 or a typical PKC (Protein Kinase-C), channel the TRAF signal to SEK1 and MKK7, the upstream activating kinases of JNK (Ref.4). TRAF6 also provides a functional connection between RANK signaling and the activation of c-Src kinase, Akt/ PKB (Protein Kinase- B), the ERKs (Extracellular Signal Regulated Kinase) and PI3K (Phosphatidylinositol-3 Kinase) (Ref.1). Recruitment of TRAF2 by TNFR-related proteins TRADD-FADD also result in increased levels of intracellular ROS (Reactive Oxygen Species) generated in mitochondria, which results in damage of lipids and proteins by oxidation. Consistent with its anti-apoptotic effects, BCLXL efficiently blocks TRAF2-mediated ROS generation in mitochondria without interfering with TRAF2-mediated activation of NF-κB (Ref.8). Other intracellular adaptor proteins that interact with TRAF proteins and regulate the function of TRAF proteins are TANK/ITRAF (TRAF-Associated and NF-κB Activator), TRIP (TRAF-Interacting Protein); protein kinases such as NIK (NF-κB-Inducing Kinase), NIKA20 and RIP2. The cytokine-induced Zn2+ finger protein A20 binds the TD of TRAF1, TRAF2 and TRAF6 and inhibits the NF-κB activation by TRAF2 and TRAF6. The signaling adaptor molecules also mediate the NF-κB activation by IL-1 receptor, and two lipopolysaccharide receptors: TLRs (Toll-like receptors) and the neurotrophin receptor p75(NTR) (Ref.4). As members of the TNFR family, BCMA (B-Cells Maturation Antigen) and TACI (Transmembrane Activator and Cyclophilin Ligand Interactor) also interact with TRAF family members after binding of APRIL (a proliferation inducing ligand) and BAFF (B-Cell Activation Factor) to transduce signals for NF-κB activation and MAPK pathways.

The TRAFs have emerged as the major signal transducers for the TNF receptor superfamily and the IL-1R/TLR superfamily. TRAFs are also involved in the signal transduction of the Epstein-Barr Virus transforming protein LMP1 (Latent Membrane Protein-1). Thus, different TRAF proteins collectively play distinct roles in signaling through CD40, LMP1, and other TNFR family members in a wide range of biological functions, such as adaptive and innate immunity, embryonic development, stress response and bone metabolism through the induction of cell survival, proliferation, differentiation and death. In Drosophila, TRAFs are essential for dorsoventral polarization and innate host defense by the signal transduction initiated through the Toll receptor (Ref.7).

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