| Structural highlights
Function
TRAF3_MOUSE Regulates pathways leading to the activation of NF-kappa-B and MAP kinases, and plays a central role in the regulation of B-cell survival. Part of signaling pathways leading to the production of cytokines and interferon. Required for normal antibody isotype switching from IgM to IgG. Plays a role T-cell dependent immune responses. Plays a role in the regulation of antiviral responses. Is an essential constituent of several E3 ubiquitin-protein ligase complexes. May have E3 ubiquitin-protein ligase activity and promote 'Lys-63'-linked ubiquitination of target proteins. Inhibits activation of NF-kappa-B in response to LTBR stimulation. Inhibits TRAF2-mediated activation of NF-kappa-B. Down-regulates proteolytic processing of NFKB2, and thereby inhibits non-canonical activation of NF-kappa-B. Promotes ubiquitination and proteasomal degradation of MAP3K14.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
The TRAF [tumor necrosis factor receptor-associated factor] family of cytoplasmic adaptor proteins link cell-surface receptors to intracellular signaling pathways that regulate innate and adaptive immune responses. In response to activation of RIG-I (retinoic acid-inducible gene I), a component of a pattern recognition receptor that detects viruses, TRAF3 binds to the adaptor protein Cardif [caspase activation and recruitment domain (CARD) adaptor-inducing interferon-beta (IFN-beta)], leading to induction of type I IFNs. We report the crystal structures of the TRAF domain of TRAF5 and that of TRAF3 bound to a peptide from the TRAF-interacting motif of Cardif. By comparing these structures, we identified two residues located near the Cardif binding pocket in TRAF3 (Tyr(440) and Phe(473)) that potentially contributed to Cardif recognition. In vitro and cellular experiments showed that forms of TRAF5 with mutation of the corresponding residues to those of TRAF3 had TRAF3-like antiviral activity. Our results provide a structural basis for the critical role of TRAF3 in activating RIG-I-mediated IFN production.
Single Amino Acid Substitutions Confer the Antiviral Activity of the TRAF3 Adaptor Protein onto TRAF5.,Zhang P, Reichardt A, Liang H, Aliyari R, Cheng D, Wang Y, Xu F, Cheng G, Liu Y Sci Signal. 2012 Nov 13;5(250):ra81. doi: 10.1126/scisignal.2003152. PMID:23150880[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Oganesyan G, Saha SK, Guo B, He JQ, Shahangian A, Zarnegar B, Perry A, Cheng G. Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature. 2006 Jan 12;439(7073):208-11. Epub 2005 Nov 23. PMID:16306936 doi:http://dx.doi.org/10.1038/nature04374
- ↑ Hacker H, Redecke V, Blagoev B, Kratchmarova I, Hsu LC, Wang GG, Kamps MP, Raz E, Wagner H, Hacker G, Mann M, Karin M. Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature. 2006 Jan 12;439(7073):204-7. Epub 2005 Nov 23. PMID:16306937 doi:http://dx.doi.org/10.1038/nature04369
- ↑ He JQ, Zarnegar B, Oganesyan G, Saha SK, Yamazaki S, Doyle SE, Dempsey PW, Cheng G. Rescue of TRAF3-null mice by p100 NF-kappa B deficiency. J Exp Med. 2006 Oct 30;203(11):2413-8. Epub 2006 Oct 2. PMID:17015635 doi:http://dx.doi.org/10.1084/jem.20061166
- ↑ He JQ, Saha SK, Kang JR, Zarnegar B, Cheng G. Specificity of TRAF3 in its negative regulation of the noncanonical NF-kappa B pathway. J Biol Chem. 2007 Feb 9;282(6):3688-94. Epub 2006 Dec 11. PMID:17158868 doi:http://dx.doi.org/10.1074/jbc.M610271200
- ↑ Gardam S, Sierro F, Basten A, Mackay F, Brink R. TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor. Immunity. 2008 Mar;28(3):391-401. doi: 10.1016/j.immuni.2008.01.009. Epub 2008, Feb 28. PMID:18313334 doi:http://dx.doi.org/10.1016/j.immuni.2008.01.009
- ↑ Vallabhapurapu S, Matsuzawa A, Zhang W, Tseng PH, Keats JJ, Wang H, Vignali DA, Bergsagel PL, Karin M. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nat Immunol. 2008 Dec;9(12):1364-70. doi: 10.1038/ni.1678. Epub 2008 Nov 9. PMID:18997792 doi:http://dx.doi.org/10.1038/ni.1678
- ↑ Zarnegar BJ, Wang Y, Mahoney DJ, Dempsey PW, Cheung HH, He J, Shiba T, Yang X, Yeh WC, Mak TW, Korneluk RG, Cheng G. Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol. 2008 Dec;9(12):1371-8. doi: 10.1038/ni.1676. Epub 2008 Nov 9. PMID:18997794 doi:http://dx.doi.org/10.1038/ni.1676
- ↑ Jabara HH, Weng Y, Sannikova T, Geha RS. TRAF2 and TRAF3 independently mediate Ig class switching driven by CD40. Int Immunol. 2009 Apr;21(4):477-88. doi: 10.1093/intimm/dxp013. Epub 2009 Feb 19. PMID:19228877 doi:http://dx.doi.org/10.1093/intimm/dxp013
- ↑ Tseng PH, Matsuzawa A, Zhang W, Mino T, Vignali DA, Karin M. Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat Immunol. 2010 Jan;11(1):70-5. doi: 10.1038/ni.1819. Epub 2009 Nov 8. PMID:19898473 doi:http://dx.doi.org/10.1038/ni.1819
- ↑ Xu Y, Cheng G, Baltimore D. Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses. Immunity. 1996 Nov;5(5):407-15. PMID:8934568
- ↑ Zhang P, Reichardt A, Liang H, Aliyari R, Cheng D, Wang Y, Xu F, Cheng G, Liu Y. Single Amino Acid Substitutions Confer the Antiviral Activity of the TRAF3 Adaptor Protein onto TRAF5. Sci Signal. 2012 Nov 13;5(250):ra81. doi: 10.1126/scisignal.2003152. PMID:23150880 doi:http://dx.doi.org/10.1126/scisignal.2003152
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