TRAF6 and the three C-terminal lysine sites on IRF7 are required for its ubiquitination-mediated activation by the tumor necrosis factor receptor family member latent membrane protein 1.

Molecular and Cellular Biology
Shunbin NingJ S Pagano

Abstract

We have recently shown that interferon regulatory factor 7 (IRF7) is activated by Epstein-Barr virus latent membrane protein 1 (LMP1), a member of the tumor necrosis factor receptor (TNFR) superfamily, through receptor-interacting protein-dependent K63-linked ubiquitination (L. E. Huye, S. Ning, M. Kelliher, and J. S. Pagano, Mol. Cell. Biol. 27:2910-2918, 2007). In this study, with the use of small interfering RNA and TNFR-associated factor 6 (TRAF6) knockout cells, we first show that TRAF6 and its E3 ligase activity are required for LMP1-stimulated IRF7 ubiquitination. In Raji cells which are latently infected and express high levels of LMP1 and IRF7 endogenously, expression of a TRAF6 small hairpin RNA construct reduces endogenous ubiquitination and endogenous activity of IRF7. In TRAF6(-/-) mouse embryonic fibroblasts, reconstitution with TRAF6 expression, but not with TRAF6(C70A), which lacks the E3 ligase activity, recovers LMP1's ability to stimulate K63-linked ubiquitination of IRF7. Further, we identify IRF7 as a substrate for TRAF6 E3 ligase and show that IRF7 is ubiquitinated by TRAF6 at multiple sites both in vitro and in vivo. Most important, we determine that the last three C-terminal lysine sites (positions 444, ...Continue Reading

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Citations

Jan 6, 2010·Cancer Immunology, Immunotherapy : CII·David SavitskyTadatsugu Taniguchi
Apr 16, 2010·Journal of Virology·Shunbin Ning, Joseph S Pagano
Apr 22, 2009·Molecular and Cellular Biology·Suzanne PazJohn Hiscott
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Mar 25, 2011·Herpesviridae·Shunbin Ning
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Jan 11, 2012·Arthritis and Rheumatism·Bahram NamjouSang-Cheol Bae
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Dec 18, 2012·Oncoimmunology·Hideyuki YanaiTadatsugu Taniguchi
Jul 6, 2016·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Giulia MarsiliAngela Battistini
Aug 24, 2016·Reviews in Medical Virology·Jin GanQiliang Cai
Dec 5, 2017·AIMS Allergy and Immunology·Ling Wang, Shunbin Ning
May 8, 2015·Journal of Virology·Gretchen L BentzJoseph S Pagano
Dec 7, 2018·The Journal of Immunology : Official Journal of the American Association of Immunologists·Long-Feng LuYong-An Zhang
Jan 22, 2014·Nature Reviews. Immunology·Paul N Moynagh

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