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Journal of Virology, December 2001, p. 12393-12401, Vol. 75, No. 24
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.24.12393-12401.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Intracellular Signaling Molecules Activated by Epstein-Barr Virus for Induction of Interferon Regulatory Factor 7

Luwen Zhang,1,2,* Lihong Wu,1 Ke Hong,1 and Joseph S. Pagano1,2,3,*

Lineberger Comprehensive Cancer Center1, Department of Medicine,3 and Department of Microbiology and Immunology,2 University of North Carolina, Chapel Hill, North Carolina 27599-7295

Received 21 May 2001/Accepted 19 September 2001

Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) is the principal oncogenic protein in the EBV transformation process. LMP-1 induces the expression of interferon regulatory factor 7 (IRF-7) and activates IRF-7 protein by phosphorylation and nuclear translocation. LMP-1 is an integral membrane protein with two regions in its C terminus that initiate signaling processes, the C-terminal activator regions 1 (CTAR-1) and CTAR-2. Here, genetic analysis of LMP-1 has determined that the PXQXT motif that governs the interaction between LMP-1 CTAR-1 and tumor necrosis factor receptor-associated factors (TRAFs) is needed to induce the expression of IRF-7. Mutations in the PXQXT motif in CTAR-1 that disrupt the interaction between LMP-1 and TRAFs abolished the induction of IRF-7. Also, dominant-negative mutants of TRAFs inhibited the induction of IRF-7 by CTAR-1. The last three amino acids (YYD) of CTAR-2 are also important for the induction of IRF-7. When both PXQXT and YYD were mutated (LMP-DM), the LMP-1 mutant failed to induce IRF-7. Also, LMP-DM blocked the induction of IRF-7 by wild-type LMP-1. These data strongly suggest that both CTAR-1 and CTAR-2 of LMP-1 independently induce the expression of IRF-7. In addition, NF-kappa B is involved in the induction of IRF-7. A superrepressor of Ikappa B (sr-Ikappa B) could block the induction of IRF-7 by LMP-1, and overexpression of NF-kappa B (p65 plus p50) could induce the expression of IRF-7. In addition, we have found that human IRF-7 is a stable protein, and sodium butyrate, a modifier of chromatin structure, induces IRF-7.

* Corresponding author. Mailing address for Joseph Pagano: Lineberger Comprehensive Cancer Center, University of North Carolina, Campus Box 7295, Chapel Hill, NC 27599. Phone: (919) 966-1183. Fax: (919) 966-9673. E-mail: joseph_pagano{at}med.unc.edu. Present address for Luwen Zhang: Nebraska Center for Virology, UNL Biological Sciences, E141 Beadle Center, 19th and Vine St., Lincoln, NE 68588-0666. Phone: (402) 472-5905. Fax: (402) 472-8722. E-mail: lzhang2{at}unlnotes.unl.edu.

Journal of Virology, December 2001, p. 12393-12401, Vol. 75, No. 24
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.24.12393-12401.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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