Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, 1600 SW Archer Rd., ARB Rm. R4-295, P.O. Box 100332, Gainesville, FL 32610, USA.
J Virol. 2010 Apr;84(7):3287-302. doi: 10.1128/JVI.02020-09. Epub 2010 Jan 27.
Viruses have evolved an assortment of mechanisms for regulating the Akt signaling pathway to establish a cellular environment more favorable for viral replication. Myxoma virus (MYXV) is a rabbit-specific poxvirus that encodes many immunomodulatory factors, including an ankyrin repeat-containing host range protein termed M-T5 that functions to regulate tropism of MYXV for rabbit lymphocytes and certain human cancer cells. MYXV permissiveness in these human cancer cells is dependent upon the direct interaction between M-T5 and Akt, which has been shown to induce the kinase activity of Akt. In this study, an array of compounds that selectively manipulate Akt signaling was screened and we show that only a subset of Akt inhibitors significantly decreased the ability of MYXV to replicate in previously permissive human cancer cells. Furthermore, reduced viral replication efficiency was correlated with lower levels of phosphorylated Akt. In contrast, the PP2A-specific phosphatase inhibitor okadaic acid promoted increased Akt kinase activation and rescued MYXV replication in human cancer cells that did not previously support viral replication. Finally, phosphorylation of Akt at residue Thr308 was shown to dictate the physical interaction between Akt and M-T5, which then leads to phosphorylation of Ser473 and permits productive MYXV replication in these human cancer cells. The results of this study further characterize the mechanism by which M-T5 exploits the Akt signaling cascade and affirms this interaction as a major tropism determinant that regulates the replication efficiency of MYXV in human cancer cells.
病毒进化出了多种调节 Akt 信号通路的机制，以建立更有利于病毒复制的细胞环境。兔粘液瘤病毒（MYXV）是一种专门感染兔子的痘病毒，它编码了许多免疫调节因子，包括一种含有锚蛋白重复序列的宿主范围蛋白 M-T5，该蛋白的功能是调节 MYXV 对兔子淋巴细胞和某些人类癌细胞的趋向性。在这些人类癌细胞中，MYXV 的允许性取决于 M-T5 和 Akt 之间的直接相互作用，已经表明该相互作用会诱导 Akt 的激酶活性。在这项研究中，筛选了一系列选择性操纵 Akt 信号的化合物，我们发现只有一小部分 Akt 抑制剂显著降低了 MYXV 在先前允许的人类癌细胞中复制的能力。此外，病毒复制效率的降低与磷酸化 Akt 的水平降低相关。相比之下，PP2A 特异性磷酸酶抑制剂 okadaic 酸促进 Akt 激酶的激活，并挽救了先前不支持病毒复制的人类癌细胞中 MYXV 的复制。最后，Akt 在残基 Thr308 处的磷酸化决定了 Akt 和 M-T5 之间的物理相互作用，从而导致 Ser473 的磷酸化，并允许 MYXV 在这些人类癌细胞中进行有效的复制。这项研究的结果进一步描述了 M-T5 利用 Akt 信号级联的机制，并证实了这种相互作用是调节 MYXV 在人类癌细胞中复制效率的主要趋向性决定因素。
