Attenuation of Rabies Virulence: Takeover by the Cytoplasmic Domain of Its Envelope Protein
Attenuation of Rabies Virulence: Takeover by the Cytoplasmic Domain of Its Envelope Protein
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DOI：
10.1126/scisignal.2000510
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发表时间：
2010-01-19
影响因子：
7.3
通讯作者：
Lafon, Monique
中科院分区：
文献类型：
--
作者：
Prehaud, Christophe;Wolff, Nicolas;Lafon, Monique
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）招募的细胞伴侣。神经元的存活需要选择性关联的PDZ-BS的G与PDZ结构域的两个密切相关的丝氨酸-苏氨酸激酶MAST 1和MAST 2。在这里，我们发现PDZ-BS中的单个氨基酸变化触发了受感染神经元的凋亡性死亡，并使G能够与其他PDZ伙伴，特别是酪氨酸磷酸酶PTPN 4相互作用。PTPN 4的敲低消除了病毒介导的细胞凋亡。因此，我们建议狂犬病病毒的减毒需要扩大与G相互作用的宿主PDZ蛋白的集合，这干扰了受感染神经元存活所需的微调稳态。
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.