HGNC Approved Gene Symbol: TRAF5
Cytogenetic location: 1q32.3 Genomic coordinates (GRCh38) : 1:211,326,635-211,374,946 (from NCBI)
Tumor necrosis factor (TNF; 191160) receptor-associated factors (TRAFs), such as TRAF5, are signal transducers for members of the TNF receptor superfamily (see 191190). TRAF proteins are composed of an N-terminal cysteine/histidine-rich region containing zinc RING and/or zinc finger motifs, a coiled-coil (leucine zipper) motif, and a homologous region in the C terminus that defines the TRAF family, the TRAF domain. The TRAF domain is involved in self-association and receptor binding (Nakano et al., 1996).
By degenerative oligonucleotide PCR amplification, Nakano et al. (1996) identified Traf5 in the mouse. Nakano et al. (1997) cloned the human TRAF homolog by cross hybridization with mouse TRAF5 cDNA. Their human cDNA has a 557-amino acid open reading frame that exhibits 80% identity to mouse TRAF5 at the amino acid level. Northern blot analysis revealed that human TRAF5 mRNA is expressed in all visceral organs. Western blotting revealed that the human protein is abundantly expressed in a human follicular dendritic cell line, and to a lesser degree in several tumor cell lines.
Nakano et al. (1996) showed that mouse Traf5 specifically interacts with the lymphotoxin-beta receptor (600979) and activates the transcription factor NF-kappa-B (NFKB; see 164011).
By in vitro binding, immunoprecipitation, immunoblot, and yeast 2-hybrid analyses, Aizawa et al. (1997) showed that TRAF2 (601895) and TRAF5 interact with overlapping but distinct sequences in the C-terminal region of CD30 (153243) and mediate the activation of NFKB.
By interspecific backcross mapping, Nakano et al. (1997) showed that Traf5 is located in the distal region of mouse chromosome 1, which shares homology with human 1q. Fluorescence in situ hybridization confirmed the regional localization of human TRAF5 to chromosome 1q32.
To investigate the functional role of Traf5 in vivo, Nakano et al. (1999) generated Traf5-deficient mice by gene targeting. They found that Traf5 -/- B lymphocytes show defects in proliferation and upregulation of various surface molecules, including CD23 (151445), CD54 (147840), CD80 (112203), CD86 (601020), and FAS (134637) in response to CD40 (109535) stimulation. Moreover, in vitro Ig production by Traf5 -/- T lymphocytes stimulated with anti-CD40 plus IL4 (147780) was reduced substantially. CD27-mediated costimulatory signal also was impaired in Traf5 -/- T lymphocytes. Collectively, these results demonstrated that Traf5 is involved in CD40- and CD27-mediated signaling.
So et al. (2004) found that Ox40 (TNFRSF4; 600315) stimulation of Cd4 (186940) T cells from Traf5 -/- mice resulted in a profound Th2 phenotype with elevated levels of Il4 and Il5 (147850). Immunization of Traf5 -/- mice with protein plus agonistic anti-Ox40 also resulted in enhanced Th2 development. Lung inflammation in a mouse model of asthma was more pronounced in Traf5 -/- mice and was characterized by eosinophilia, airway hyperreactivity, and increased levels of Th2 cytokines and plasma IgE. So et al. (2004) concluded that TRAF5 pathways modulate the Th1/Th2 balance and limit the induction of Th2 responses.
Kraus et al. (2009) noted that the Epstein-Barr virus-encoded latent membrane protein-1 (LMP1) is a functional oncogenic mimic of CD40 and is expressed as a 6-transmembrane receptor on the cell surface. They created mice expressing a mouse Cd40-LMP1 transgene on a Cd40 -/- background that also either expressed or lacked Traf5 and observed grossly enlarged spleens and lymph nodes in LMP1-positive Traf5 +/+ mice, but smaller spleens and nodes in LMP1-positive Traf5 -/- mice. The absence of Traf5 in LMP1-positive mice reversed the elevated levels of serum Il6 and anti-double-stranded DNA antibodies, as well as the increased numbers of germinal center B cells, seen in LMP1-positive Traf5 +/+ mice. Similarly, anti-CD40 stimulated LMP1-positive Traf5 +/+ B lymphocytes secreted more Tnfa and Il17 (603149), but not Il10 (124092) or Il12 (161560), than LMP1-positive Traf5 -/- B lymphocytes. These LMP1-induced signaling effects in Traf5 +/+ mice depended on Jnk (MAPK8; 601158) activation, which was absent in LMP1-positive Traf5 -/- B lymphocytes. Kraus et al. (2009) concluded that TRAF5 has a critical role in LMP1-mediated JNK signaling and that TRAF5 is required for signaling by a specific receptor both in vitro and in vivo.
Aizawa, S., Nakano, H., Ishida, T., Horie, R., Nagai, M., Ito, K., Yagita, H., Okumura, K., Inoue, J., Watanabe, T. Tumor necrosis factor receptor-associated factor (TRAF) 5 and TRAF2 are involved in CD30-mediated NF-kappa-B activation. J. Biol. Chem. 272: 2042-2045, 1997. [PubMed: 8999898] [Full Text: https://doi.org/10.1074/jbc.272.4.2042]
Kraus, Z. J., Nakano, H., Bishop, G. A. TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40. Proc. Nat. Acad. Sci. 106: 17140-17145, 2009. [PubMed: 19805155] [Full Text: https://doi.org/10.1073/pnas.0903786106]
Nakano, H., Oshima, H., Chung, W., Williams-Abbott, L., Ware, C. F., Yagita, H., Okumura, K. TRAF5, an activator of NF-kappaB and putative signal transducer for the lymphotoxin-beta receptor. J. Biol. Chem. 271: 14661-14664, 1996. [PubMed: 8663299] [Full Text: https://doi.org/10.1074/jbc.271.25.14661]
Nakano, H., Sakon, S., Koseki, H., Takemori, T., Tada, K., Matsumoto, M., Munechika, E., Sakai, T., Shirasawa, T., Akiba, H, Kobata, T., Santee, S. M., Ware, C. F., Renner, P. D., Taniguchi, M., Yagita, H., Okumura, K. Targeted disruption of Traf5 gene causes defects in CD40- and CD27-mediated lymphocyte activation. Proc. Nat. Acad. Sci. 96: 9803-9808, 1999. [PubMed: 10449775] [Full Text: https://doi.org/10.1073/pnas.96.17.9803]
Nakano, H., Shindo, M., Yamada, K., Yoshida, M. C., Santee, S. M., Ware, C. F., Jenkins, N. A., Gilbert, D. J., Yagita, H., Copeland, N. G., Okumura, K. Human TNF receptor-associated factor 5 (TRAF5): cDNA cloning, expression and assignment of the TRAF5 gene to chromosome 1q32. Genomics 42: 26-32, 1997. [PubMed: 9177772] [Full Text: https://doi.org/10.1006/geno.1997.4697]
So, T., Salek-Ardakani, S., Nakano, H., Ware, C. F., Croft, M. TNF receptor-associated factor 5 limits the induction of Th2 immune responses. J. Immun. 172: 4292-4297, 2004. [PubMed: 15034043] [Full Text: https://doi.org/10.4049/jimmunol.172.7.4292]