PIRSF015614

TNF receptor-associated factor (TRAF)

PIRSF entry
Member databasePIRSF
PIRSF typefamily
Short nameTRAF

Description

The tumor necrosis factor (TNF) receptor associated factors (TRAFs) are major signal transducers for the TNF receptor (TNFR) superfamily and the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily in mammals
[9]
. TRAFs constitute a family of genetically conserved adapter proteins found in mammals (TRAF1-6) as well as in other multicellular organisms such as Drosophila
[6]
and Caenorhabditis elegans
[3]
. TRAF2 is the prototypical member of the family. Mammalian TRAF1 and TRAF2 were the first members, initially identified by their association with TNFR2. The TRAF1/TRAF2 and TRAF3/TRAF5 gene pairs may have arisen from recent independent gene duplications, after sharing a more remote common ancestral gene. TRAF4 and TRAF6 precursor genes may have arisen earlier during evolution, with the divergence of the TRAF6 precursor occurring earliest of all.

Except for TRAF1, these proteins have a general domain architecture containing one N-terminal RING finger, a variable number of TRAF-type zinc finger and C2H2 type zinc finger domains in the middle region, and one C-terminal MATH domain. TRAF1 is unique in lacking the N-terminal RING and zinc-finger domains
[2]
. This has rendered TRAF1 unable to promote TNF receptor signaling and to act as a "dominant negative" TRAF
[5]
. Also TRAF1 is a substrate for caspases activated by TNF family death receptors
[1]
. The larger C-terminal cleaved fragment can bind to and sequester TRAF2 from the TNFR1 complex, therefore modulating TNF-induced NF-kappaB activation
[8]
.

A wide range of biological functions, such as adaptive and innate immunity, embryonic development, stress response and bone metabolism, are mediated by TRAFs through the induction of cell survival, proliferation, differentiation and death. TRAFs are functionally divergent from a perspective of both upstream and downstream TRAF signal transduction pathways and of signaling-dependent regulation of TRAF trafficking. Each TRAF protein interacts with and mediates the signal transduction of multiple receptors and, in turn, each receptor utilizes multiple TRAFs for specific functions
[5]
. About 40 interaction partners of TRAF have been described thus far, including receptors, kinases, regulators and adapter proteins.

TRAF proteins can be recruited to and activated by ligand-engaged receptors in at least three distinct ways
[9]
. 1) Members of the TNFR superfamily that do not contain intracellular death domains, such as TNFR2 and CD40, recruit TRAFs directly via short sequences in their intracellular tails
[2]
. 2) Those that contain an intracellular death domain, such as TNFR1, first recruit an adapter protein, TRADD, via a death-domain?death-domain interaction. This then serves as a central platform of the TNFR1 signaling complex, which assembles TRAF2 and receptor-interacting protein (RIP, the death domain kinase) for survival signaling, and Fas-associated death domain protein and caspase-8 for the induction of apoptosis. 3) Members of the IL-1R/TLR superfamily contain a protein interaction module known as the TIR domain, which recruits, sequentially, MyD88, a TIR domain and death domain containing protein, and IRAKs, adapter Ser/Thr kinases with death domains. IRAKs in turn associate with TRAF6 to elicit signaling by interleukin-1 and pathogenic components such as lipopolysaccharide.

A common mechanism for the membrane-proximal event in TRAF signaling has been revealed by the conserved trimeric association in the crystal structure of the TRAF domain of TRAF2
[7]
.

For additional information please see
[10, 4]
.

References

1.TRAF1 is a substrate of caspases activated during tumor necrosis factor receptor-alpha-induced apoptosis. Leo E, Deveraux QL, Buchholtz C, Welsh K, Matsuzawa S, Stennicke HR, Salvesen GS, Reed JC. J. Biol. Chem. 276, 8087-93, (2001). View articlePMID: 11098060

2.A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Rothe M, Wong SC, Henzel WJ, Goeddel DV. Cell 78, 681-92, (1994). View articlePMID: 8069916

3.Identification of a TRAF (TNF receptor-associated factor) gene in Caenorhabditis elegans. Wajant H, Muhlenbeck F, Scheurich P. J. Mol. Evol. 47, 656-62, (1998). View articlePMID: 9847406

4.Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation. Banner DW, D'Arcy A, Janes W, Gentz R, Schoenfeld HJ, Broger C, Loetscher H, Lesslauer W. Cell 73, 431-45, (1993). View articlePMID: 8387891

5.Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death. Arch RH, Gedrich RW, Thompson CB. Genes Dev. 12, 2821-30, (1998). View articlePMID: 9744859

6.A Drosophila TNF-receptor-associated factor (TRAF) binds the ste20 kinase Misshapen and activates Jun kinase. Liu H, Su YC, Becker E, Treisman J, Skolnik EY. Curr. Biol. 9, 101-4, (1999). View articlePMID: 10021364

7.Structural basis for self-association and receptor recognition of human TRAF2. Park YC, Burkitt V, Villa AR, Tong L, Wu H. Nature 398, 533-8, (1999). View articlePMID: 10206649

8.Tumor necrosis factor receptor-associated factors (TRAFs). Bradley JR, Pober JS. Oncogene 20, 6482-91, (2001). View articlePMID: 11607847

9.All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. Chung JY, Park YC, Ye H, Wu H. J. Cell. Sci. 115, 679-88, (2002). View articlePMID: 11865024

10.Thermodynamic characterization of the interaction between TRAF2 and tumor necrosis factor receptor peptides by isothermal titration calorimetry. Ye H, Wu H. Proc. Natl. Acad. Sci. U.S.A. 97, 8961-6, (2000). View articlePMID: 10908665

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