Floettmann J E, Eliopoulos A G, Jones M, Young L S, Rowe M
Department of Medicine, University of Wales College of Medicine, Heath Park, Cardiff, UK.
Oncogene. 1998 Nov 5;17(18):2383-92. doi: 10.1038/sj.onc.1202144.
The Epstein-Barr virus (EBV) encoded Latent Membrane Protein-1 (LMP1) mimics a constitutively active receptor molecule, and has been shown to activate NF-kappaB and the MAPK and JNK pathways. Two regions within the cytosolic domain of LMP1 have been found to effect cell signalling. One of these, the carboxy-terminal activation region-1 (CTAR1), binds members of the TRAF family of proteins, and the other (CTAR2) binds TRADD, suggesting that LMP1 transduces signals similarly to the Tumour Necrosis Factor Receptor family of receptors. The ability to bind TRAFs, to activate NF-kappaB and the JNK pathway, to upregulate cellular genes such as CD54 (ICAM-1 adhesion molecule), and to affect cell growth and apoptosis has led to the suggestion that LMP1 signalling is similar to, or even identical to CD40. However, we now show that while ligand-induced CD40 signalling is impaired in the Jurkat T cell line, LMP1 was fully functional; therefore demonstrating that LMP1 and CD40 signalling differ. Mutated LMP1 genes, in which one or other of the CTAR1 and CTAR2 domains was non-functional, behaved more like CD40 in being unable to upregulate the CD54 cell surface marker in Jurkat cells. However, the CTAR1 domain of LMP1, which shared a TRAF-binding sequence motif with CD40, differed from CD40 in being unable to activate NF-kappaB in Jurkat. Cotransfection experiments with LMP1 mutants demonstrated that CTAR1 can cooperative with CTAR2 on separate LMP1 molecules, provided that they exist within the same oligomeric complex.
爱泼斯坦-巴尔病毒（EBV）编码的潜伏膜蛋白1（LMP1）模拟一种组成型激活的受体分子，并且已被证明可激活核因子κB以及丝裂原活化蛋白激酶（MAPK）和应激活化蛋白激酶（JNK）信号通路。已发现LMP1胞质结构域内的两个区域可影响细胞信号传导。其中之一，即羧基末端激活区域1（CTAR1），可结合TRAF家族的蛋白质成员，另一个区域（CTAR2）可结合肿瘤坏死因子受体相关死亡结构域蛋白（TRADD），这表明LMP1转导信号的方式类似于肿瘤坏死因子受体家族的受体。LMP1结合TRAFs、激活核因子κB和JNK信号通路、上调细胞基因如CD54（细胞间黏附分子1）以及影响细胞生长和凋亡的能力，提示LMP1信号传导与CD40相似，甚至相同。然而，我们现在发现，虽然在Jurkat T细胞系中配体诱导的CD40信号传导受损，但LMP1功能完全正常；因此证明LMP1和CD40信号传导不同。CTAR1和CTAR2结构域之一无功能的LMP1突变基因，在无法上调Jurkat细胞中CD54细胞表面标志物方面，表现得更像CD40。然而，LMP1的CTAR1结构域与CD40共享一个TRAF结合序列基序，但在Jurkat细胞中与CD40不同，它无法激活核因子κB。LMP1突变体的共转染实验表明，只要CTAR1存在于同一寡聚复合物中，它就可以与不同LMP1分子上的CTAR2协同作用。
