Alternative titles; symbols
HGNC Approved Gene Symbol: TRAF1
Cytogenetic location: 9q33.2 Genomic coordinates (GRCh38): 9:120,902,393-120,929,171 (from NCBI)
To determine how tumor necrosis factor (TNF; 191160) elicits cellular response, Rothe et al. (1994) searched for factors that interact with the cytoplasmic domain of TNF receptor-2 (TNFR2; 191191). They used the yeast-based 2-hybrid system to detect mouse proteins that interact with Tnfr2. They identified and cloned 2 Tnf receptor-associated factors, which they termed Traf1 and Traf2 (601895). Each of the proteins contains a C-terminal TRAF domain of approximately 230 amino acids. Traf1 and Traf2 can form both homo- and heterodimers.
Mosialos et al. (1995) identified the human homolog of TRAF1 as Epstein-Barr virus (EBV)-induced mRNA 6 (EBI6), an mRNA that is more abundant in EBV-infected B lymphoblasts than in uninfected control cells. The predicted 416-amino acid human protein is 86% identical to mouse Traf1. Both the human and mouse proteins contain N-terminal zinc finger motifs and C-terminal TRAF domains. Northern blot analysis revealed that the 2.6-kb EBI6 mRNA is expressed in lung, spleen, tonsil, and weakly in placenta.
The structural hallmark of signal-transducing proteins associated with members of the TNFR superfamily is a novel C-terminal homology region of 230 amino acids, designated the TRAF domain. This domain is involved in a variety of specific protein-protein interactions. Siemienski et al. (1997) found that the human TRAF1 gene has a total length of approximately 12 kb. It is split into 6 exons, 4 of which encode parts of the TRAF domain. Analysis of the genomic structure of the TRAF domains of TRAF2 and TRAF3 (601896) suggest that these domains are also encoded by several exons.
Siemienski et al. (1997) used fluorescence in situ hybridization to map the TRAF1 gene to 9q33-q34.
Mosialos et al. (1995) found that LMP1, the EBV-transforming protein, specifically associates with LAP1 (TRAF3) or EBI6 in B lymphoblasts. LMP1 expression redirects LAP1 and EBI6 from scattered cytoplasmic structures to LMP1 plasma membrane patches. Both LAP1 and EBI6 associated with the cytoplasmic domain of p80/TNFR2 in vivo. The authors stated that the interaction of LMP1 with the LAP1 and EBI6 TNFR-associated proteins is evidence for the role of these proteins in signaling, and links LMP1-mediated transformation to signal transduction from the TNFR family.
By flow cytometric analysis, Wang et al. (2012) demonstrated that TRAF1 levels were significantly lower in human immunodeficiency virus (HIV)-specific CD8 (see 186910) T cells from chronically infected individuals compared with those from recently infected individuals or HIV viral controllers. TRAF1 expression showed a negative correlation with PD1 (600244) expression and HIV viral load. Knockdown of TRAF1 in CD8 T cells from viral controllers resulted in diminished suppression of HIV in infected CD4 (186940) T cells, partly due to impairment of the 4-1BBL (TNFSF9; 606182)-4-1BB (TNFRSF9; 602250) pathway. IL7 (146660), as well as IL2 (147680) and IL15 (600554), but not IL21 (605384), increased TRAF1 expression in an antigen-independent manner. Using the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection, Wang et al. (2012) showed that mice lacking 4-1bbl had defects in the early, but not the late, stage of chronic LCMV infection. Treatment of LCMV-infected mice with a combination of Il7, which restored Traf1 levels in T cells of chronically infected mice, and agonist anti-4-1bb antibody at 3 weeks after infection resulted in expansion of T cells and a reduction of viral load in a Traf1-dependent manner. Mice lacking Traf1 had impaired responses to agonistic anti-4-1bb treatment. Transfer of Traf1-expressing cells at the chronic stage of infection reduced viral load. Wang et al. (2012) proposed that IL7 treatment to enhance TRAF1 expression may also increase the fitness of HIV-specific CD8 T cells.
Plenge et al. (2007) genotyped 317,503 single-nucleotide polymorphisms (SNPs) in a combined case-control study of 1,522 case subjects with rheumatoid arthritis (180300) and 1,850 matched control subjects. All patients were seropositive for autoantibodies against cyclic citrullinated peptide (CCP). Samples were from 2 datasets: the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality control filters were combined, and SNPs showing a significant association with disease were genotyped in an independent set of case subjects with anti-CCP-positive rheumatoid arthritis and in control subjects. Plenge et al. (2007) found associations with a SNP on chromosome 9, rs3761847, for all samples tested, with an odds ratio of 1.32 (95% confidence interval, 1.23 to 1.42; P = 4 x 10(-14)). This SNP is in linkage disequilibrium with 2 genes relevant to chronic inflammation: TRAF1 and C5 (120900). No coding SNP that might be responsible for this association was found.
Tsitsikov et al. (2001) generated Traf1-null mice. Although lymphocyte development was normal, T cells responded to anti-CD3 stimulation with enhanced proliferation. Through TNFR2, but not through TNFR1 (191190), they also exhibited enhanced proliferation as well as NFKB (164011) and AP1 activation. TNF-induced, lymphocyte-dependent skin necrosis occurred in Traf1 -/- mice at a suboptimal dose of the cytokine. Tsitsikov et al. (2001) concluded that TRAF1 negatively regulates TNFR2-mediated proliferation and NFKB activation.
Sabbagh et al. (2006) found that antigen-specific Cd8 (see 186910) T cells were reduced in Traf1-deficient mice during the primary and secondary responses to influenza virus infection. Flow cytometric analysis showed that stimulation with influenza peptide in vitro resulted in comparable numbers of Ifng (147570)-producing cells capable of killing influenza virus-infected target cells in wildtype and Traf1-deficient mice. There was no proliferative defect in Traf1-deficient Cd8 T cells, but they had increased levels of Bim (BCL2L11; 603827). Adoptive transfer experiments revealed decreased recovery of Traf1-deficient Cd8 T cells, which could be reversed by small interfering RNA-mediated downregulation of Bim. Sabbagh et al. (2006) concluded that increased levels of BIM in TRAF1-deficient T cells contribute to decreased survival of memory T cells in vivo.
Mosialos, G., Birkenbach, M., Yalamanchili, R., VanArsdale, T., Ware, C., Kieff, E. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80: 389-399, 1995. [PubMed: 7859281] [Full Text: https://doi.org/10.1016/0092-8674(95)90489-1]
Plenge, R. M., Seielstad, M., Padyukov, L., Lee, A. T., Remmers, E. F., Ding, B., Liew, A., Khalili, H., Chandrasekaran, A., Davies, L. R. L., Li, W., Tan, A. K. S., and 17 others. TRAF1-C5 as a risk locus for rheumatoid arthritis: a genomewide study. New Eng. J. Med. 357: 1199-1209, 2007. [PubMed: 17804836] [Full Text: https://doi.org/10.1056/NEJMoa073491]
Rothe, M., Wong, S. C., Henzel, W. J., Goeddel, D. V. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 78: 681-692, 1994. [PubMed: 8069916] [Full Text: https://doi.org/10.1016/0092-8674(94)90532-0]
Sabbagh, L., Srokowski, C. C., Pulle, G., Snell, L. M., Sedgmen, B. J., Liu, Y., Tsitsikov, E. N., Watts, T. H. A critical role for TNF receptor-associated factor 1 and Bim down-regulation in CD8 memory T cell survival. Proc. Nat. Acad. Sci. 103: 18703-18708, 2006. [PubMed: 17116875] [Full Text: https://doi.org/10.1073/pnas.0602919103]
Siemienski, K., Peters, N., Scheurich, P., Wajant, H. Organization of the human tumour necrosis factor receptor-associated factor 1 (TRAF1) gene and mapping to chromosome 9q33-34. Gene 195: 35-39, 1997. [PubMed: 9300817] [Full Text: https://doi.org/10.1016/s0378-1119(97)00147-9]
Tsitsikov, E. N., Laouini, D., Dunn, I. F., Sannikova, T. Y., Davidson, L., Alt, F. W., Geha, R. S. TRAF1 is a negative regulator of TNF signaling: enhanced TNF signaling in TRAF1-deficient mice. Immunity 15: 647-657, 2001. [PubMed: 11672546] [Full Text: https://doi.org/10.1016/s1074-7613(01)00207-2]
Wang, C., McPherson, A. J., Jones, R. B., Kawamura, K. S., Lin, G. H., Lang, P. A., Ambagala, T., Pellegrini, M., Calzascia, T., Aidarus, N., Elford, A. R., Yue, F. Y., and 9 others. Loss of the signaling adaptor TRAF1 causes CD8+ T cell dysregulation during human and murine chronic infection. J. Exp. Med. 209: 77-91, 2012. [PubMed: 22184633] [Full Text: https://doi.org/10.1084/jem.20110675]