Institut Pasteur, 75724 Paris, France.
Sci Signal. 2010 Jan 19;3(105):ra5. doi: 10.1126/scisignal.2000510.
The capacity of a rabies virus to promote neuronal survival (a signature of virulence) or death (a marker of attenuation) depends on the cellular partners recruited by the PDZ-binding site (PDZ-BS) of its envelope glycoprotein (G). Neuronal survival requires the selective association of the PDZ-BS of G with the PDZ domains of two closely related serine-threonine kinases, MAST1 and MAST2. Here, we found that a single amino acid change in the PDZ-BS triggered the apoptotic death of infected neurons and enabled G to interact with additional PDZ partners, in particular the tyrosine phosphatase PTPN4. Knockdown of PTPN4 abrogated virus-mediated apoptosis. Thus, we propose that attenuation of rabies virus requires expansion of the set of host PDZ proteins with which G interacts, which interferes with the finely tuned homeostasis required for survival of the infected neuron.
狂犬病病毒促进神经元存活（毒力标志）或死亡（减毒标志）的能力取决于其包膜糖蛋白 (G) 的 PDZ 结合位点 (PDZ-BS) 招募的细胞伙伴。神经元存活需要 G 的 PDZ-BS 与两种密切相关的丝氨酸/苏氨酸激酶 MAST1 和 MAST2 的 PDZ 结构域选择性结合。在这里，我们发现 PDZ-BS 中的单个氨基酸变化触发了感染神经元的凋亡死亡，并使 G 能够与其他 PDZ 伙伴相互作用，特别是酪氨酸磷酸酶 PTPN4。PTPN4 的敲低消除了病毒介导的凋亡。因此，我们提出狂犬病病毒的衰减需要扩展 G 相互作用的宿主 PDZ 蛋白组，这会干扰感染神经元存活所需的精细的动态平衡。
