期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：1
页码：141-146
DOI：10.1073/pnas.2237183100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1)-induced NF-{kappa}B activation is important for infected cell survival. LMP1 activates NF-{kappa}B, in part, by engaging tumor necrosis factor (TNF) receptor-associated factors (TRAFs), which also mediate NF-{kappa}B activation from LT{beta}R and CD40. LT{beta}R and CD40 activation of p100/NF-{kappa}B2 is now known to be NIK/IKK-dependent and IKK{beta}/IKK{gamma} independent. In the experiments described here, we found that EBV LMP1 induced p100/NF-{kappa}B2 processing in human lymphoblasts and HEK293 cells. LMP1-induced p100 processing was NIK/IKK dependent and IKK{beta}/IKK{gamma} independent. Furthermore, the LMP1 TRAF-binding site was required for p100 processing and p52 nuclear localization, whereas the LMP1 death domain-binding site was not. Moreover, the LMP1 TRAF-binding site preferentially caused RelB nuclear accumulation. In murine embryo fibroblasts (MEFs), IKK{beta} was essential for LMP1 up-regulation of macrophage inflammatory protein (MIP)-2, TNF, I-TAC, ELC, MIG, and CXCR4 RNAs. Interestingly, in IKK knockout MEFs, LMP1 hyperinduced MIP-2, TNF, and I-TAC expression, consistent with a role for IKK in down-modulating canonical IKK{beta} activation or its effects. In contrast, LMP1 failed to up-regulate CXCR4 and MIG RNA in IKK knockout MEFs, indicating a dependence on noncanonical IKK activation. Furthermore, LMP1 up-regulation of MIP-2 RNA in MEFs was both IKK{beta}- and IKK{gamma}-dependent, whereas LMP1 upregulation of MIG and I-TAC RNA was fully IKK{gamma} independent. Thus, LMP1 induces typical canonical IKK{beta}/IKK{gamma}-dependent, atypical canonical IKK{beta}-dependent/IKK{gamma}-independent, and noncanonical NIK/IKK-dependent NF-{kappa}B activations; NIK/IKK-dependent NF-{kappa}B activation is principally mediated by the LMP1 TRAF-binding site.
