Intracellular signaling molecules activated by Epstein-Barr virus for induction of interferon regulatory factor 7.
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-kappaB is involved in the induction of IRF-7. A superrepressor of IkappaB (sr-IkappaB) could block the induction of IRF-7 by LMP-1, and overexpression of NF-kappaB (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.
Zhang
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L
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA. lzhang2@unlnotes.unl.edu
Wu
L
L
Hong
K
K
Pagano
J S
JS
D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D002352:Carrier Proteins / Q000737:chemistry / Q000502:physiology; D002460:Cell Line; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000737:chemistry; D006207:Half-Life; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D050839:Interferon Regulatory Factor-7; D047908:Intracellular Signaling Peptides and Proteins; D053616:Janus Kinase 3; D060588:LIM Domain Proteins; D016328:NF-kappa B / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011506:Proteins / Q000502:physiology; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D016328:NF-kappa B; C484380:PDLIM7 protein, human; D011506:Proteins; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3