Most TRAFs, with the exception of TRAF1, contain an N-terminal RING finger domain, followed by a variable number of zinc fingers. Therefore, one important role of TRAFs is to serve as adaptor proteins in the assembly of receptor-associated signaling complexes, linking upstream receptors to downstream effector enzymes. For example, the eight-stranded β-sandwich structure of the TRAF-C domain mediates the interaction with receptors, and the minor structural differences in this domain among TRAFs (as revealed by X-ray crystallography) define the specificity of each TRAF binding to various receptors. The TRAF domain mediates protein-protein interactions, including TRAF oligomerization as well as interactions with upstream regulators and downstream effectors. The distinctive feature of all TRAF proteins is a C-terminal TRAF domain, which is composed of an N-terminal coiled-coil region (TRAF-N) and a C-terminal β-sandwich (TRAF-C). Although a novel protein was named TRAF7, this claim is controversial as the protein does not have the TRAF homology domain that defines the TRAF family (Figure 1). There are six known members of the TRAF family (TRAF1 to 6) in mammals. The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of intracellular proteins were originally identified as signaling adaptors that bind directly to the cytoplasmic regions of receptors of the TNF-R superfamily. This review presents an overview of the current knowledge of TRAFs, with an emphasis on recent findings concerning TRAF molecules in signaling and in human diseases. Notably, mounting evidence implicates TRAFs in the pathogenesis of human diseases such as cancers and autoimmune diseases, which has sparked new appreciation and interest in TRAF research.
Compelling evidence obtained from germ-line and cell-specific TRAF-deficient mice demonstrates that each TRAF plays indispensable and non-redundant physiological roles, regulating innate and adaptive immunity, embryonic development, tissue homeostasis, stress response, and bone metabolism. TRAF-dependent signaling pathways typically lead to the activation of nuclear factor-κBs (NF-κBs), mitogen-activated protein kinases (MAPKs), or interferon-regulatory factors (IRFs). In addition to their role as adaptor proteins, most TRAFs also act as E3 ubiquitin ligases to activate downstream signaling events. These include Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), T cell receptor, IL-1 receptor family, IL-17 receptors, IFN receptors and TGFβ receptors. The past decade has witnessed rapid expansion of receptor families identified to employ TRAFs for signaling.
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