Sylla B S, Hung S C, Davidson D M, Hatzivassiliou E, Malinin N L, Wallach D, Gilmore T D, Kieff E, Mosialos G
Departments of Microbiology and Molecular Genetics and Medicine, Harvard Medical School and Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA.
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10106-11. doi: 10.1073/pnas.95.17.10106.
The Epstein-Barr virus oncoprotein latent infection membrane protein 1 (LMP1) is a constitutively aggregated pseudo-tumor necrosis factor receptor (TNFR) that activates transcription factor NF-kappaB through two sites in its C-terminal cytoplasmic domain. One site is similar to activated TNFRII in associating with TNFR-associated factors TRAF1 and TRAF2, and the second site is similar to TNFRI in associating with the TNFRI death domain interacting protein TRADD. TNFRI has been recently shown to activate NF-kappaB through association with TRADD, RIP, and TRAF2; activation of the NF-kappaB-inducing kinase (NIK); activation of the IkappaB alpha kinases (IKKalpha and IKKbeta); and phosphorylation of IkappaB alpha. IkappaB alpha phosphorylation on Ser-32 and Ser-36 is followed by its degradation and NF-kappaB activation. In this report, we show that NF-kappaB activation by LMP1 or by each of its effector sites is mediated by a pathway that includes NIK, IKKalpha, and IKKbeta. Dominant negative mutants of NIK, IKKalpha, or IKKbeta substantially inhibited NF-kappaB activation by LMP1 or by each of its effector sites.
爱泼斯坦-巴尔病毒癌蛋白潜伏感染膜蛋白1（LMP1）是一种组成性聚集的假肿瘤坏死因子受体（TNFR），它通过其C末端细胞质结构域中的两个位点激活转录因子NF-κB。一个位点类似于活化的TNFRII，可与TNFR相关因子TRAF1和TRAF2结合，第二个位点类似于TNFRI，可与TNFRI死亡结构域相互作用蛋白TRADD结合。最近研究表明，TNFRI通过与TRADD、RIP和TRAF2结合来激活NF-κB；激活NF-κB诱导激酶（NIK）；激活IkappaBα激酶（IKKα和IKKβ）；以及使IkappaBα磷酸化。IkappaBα在Ser-32和Ser-36处磷酸化后会发生降解并激活NF-κB。在本报告中，我们表明LMP1或其每个效应位点激活NF-κB是由包括NIK、IKKα和IKKβ的信号通路介导的。NIK、IKKα或IKKβ的显性负性突变体可显著抑制LMP1或其每个效应位点对NF-κB的激活。
