Song Yoon-Jae, Izumi Kenneth M, Shinners Nicholas P, Gewurz Benjamin E, Kieff Elliott
Department of Microbiology, Channing Laboratory/Brigham & Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18448-53. doi: 10.1073/pnas.0809933105. Epub 2008 Nov 18.
Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1), a constitutively aggregated and activated pseudoreceptor, activates IFN regulatory factor 7 (IRF7) through RIP1. We now report that the LMP1 cytoplasmic carboxyl terminal amino acids 379-386 bound IRF7 and activated IRF7. IRF7 activation required TRAF6 and RIP1, but not TRAF2 or TRAF3. LMP1 Y(384)YD(386), which are required for TRADD and RIP1 binding and for NF-kappaB activation, were not required for IRF7 binding, but were required for IRF7 activation, implicating signaling through TRADD and RIP1 in IRF7 activation. Association with active LMP1 signaling complexes was also critical for IRF7 activation because (i) a dominant-negative IRF7 bound to LMP1, blocked IRF7 association and activation, but did not inhibit LMP1 induced NF-kappaB or TBK1 or Sendai virus-mediated IFN stimulated response element activation; and (ii) two different LMP1 transmembrane domain mutants, which fail to aggregate, each bound IRF7 and prevented LMP1 from binding and activating IRF7 in the same cell, but did not prevent NF-kappaB activation. Thus, efficient IRF7 activation required association with LMP1 CTAR2 in proximity to LMP1 CTAR2 mediated kinase activation sites.
爱泼斯坦-巴尔病毒（EBV）潜伏感染膜蛋白1（LMP1）是一种组成性聚集并激活的假受体，它通过RIP1激活干扰素调节因子7（IRF7）。我们现在报告，LMP1细胞质羧基末端氨基酸379 - 386与IRF7结合并激活IRF7。IRF7的激活需要TRAF6和RIP1，但不需要TRAF2或TRAF3。TRADD和RIP1结合以及NF-κB激活所必需的LMP1 Y(384)YD(386)，对于IRF7结合不是必需的，但对于IRF7激活是必需的，这表明通过TRADD和RIP1的信号传导参与了IRF7的激活。与活跃的LMP1信号复合物的结合对于IRF7激活也至关重要，因为（i）一种显性负性IRF7与LMP1结合，阻断了IRF7的结合和激活，但不抑制LMP1诱导的NF-κB或TBK1或仙台病毒介导的干扰素刺激反应元件激活；以及（ii）两种不同的LMP1跨膜结构域突变体，它们不能聚集，各自与IRF7结合并阻止LMP1在同一细胞中结合和激活IRF7，但不阻止NF-κB激活。因此，有效的IRF7激活需要在靠近LMP1 CTAR2介导的激酶激活位点处与LMP1 CTAR2结合。
