Ikeda Masato, Longnecker Richard
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Virology. 2009 Mar 1;385(1):183-91. doi: 10.1016/j.virol.2008.11.018. Epub 2008 Dec 10.
Latent membrane protein 2A (LMP2A) of Epstein-Barr virus (EBV) plays a key role in regulating viral latency and EBV pathogenesis by functionally mimicking signals induced by the B-cell receptor (BCR) altering normal B cell development. As c-Cbl ubiquitin ligase (E3) is a critical negative regulator in the BCR signal pathway, the role of c-Cbl in the function and formation of the LMP2A signalosome was examined. c-Cbl promoted LMP2A degradation through ubiquitination, specifically degraded the Syk protein tyrosine kinase in the presence of LMP2A, and inhibited LMP2A induction of the EBV lytic cycle. Our earlier studies indicated that LMP2A-dependent Lyn degradation was mediated by Nedd4-family E3s in LMP2A expressing cells. Combine with these new findings, we propose a model in which c-Cbl and Nedd4-family E3s cooperate to degrade target proteins at discrete steps in the function of the LMP2A signalosome.
爱泼斯坦-巴尔病毒（EBV）的潜伏膜蛋白2A（LMP2A）通过在功能上模拟B细胞受体（BCR）诱导的信号来改变正常B细胞发育，从而在调节病毒潜伏和EBV发病机制中发挥关键作用。由于c-Cbl泛素连接酶（E3）是BCR信号通路中的关键负调节因子，因此研究了c-Cbl在LMP2A信号小体的功能和形成中的作用。c-Cbl通过泛素化促进LMP2A降解，在LMP2A存在的情况下特异性降解Syk蛋白酪氨酸激酶，并抑制LMP2A诱导的EBV裂解周期。我们早期的研究表明，LMP2A依赖的Lyn降解是由表达LMP2A的细胞中的Nedd4家族E3介导的。结合这些新发现，我们提出了一个模型，其中c-Cbl和Nedd4家族E3在LMP2A信号小体功能的离散步骤中协同降解靶蛋白。
