PDF(Pubmed)
Abstract：
Stress granules (SGs), formed by untranslated messenger ribonucleoproteins (mRNPs) during cellular stress in eukaryotes, have been linked to flavivirus interference without clear understanding. This study reveals the role of Zika virus (ZIKV) NS2B as a scaffold protein mediating interaction between protein phosphatase 1α (PP1α) and eukaryotic initiation factor 2α (eIF2α). This interaction promotes eIF2α dephosphorylation by PP1α, inhibiting SG formation. The NS2B-PP1α complex exhibits remarkable stability, resisting ubiquitin-induced degradation and amplifying eIF2α dephosphorylation, thus promoting ZIKV replication. In contrast, the NS2BV35A mutant, interacting exclusively with eIF2α, fails to inhibit SG formation, resulting in reduced viral replication and diminished impact on brain organoid growth. These findings reveal PP1α\'s dual role in ZIKV infection, inducing interferon production as an antiviral factor and suppressing SG formation as a viral promoter. Moreover, we found that NS2B also serves as a versatile mechanism employed by flaviviruses to counter host antiviral defenses, primarily by broadly inhibiting SG formation. This research advances our comprehension of the complex interplay in flavivirus-host interactions, offering potential for innovative therapeutic strategies against flavivirus infections.
摘要：
应力颗粒(SGs)，由真核生物细胞应激期间的非翻译信使核糖核蛋白（mRNPs）形成，在没有明确了解的情况下与黄病毒干扰有关。本研究揭示了寨卡病毒（ZIKV）NS2B作为支架蛋白介导蛋白磷酸酶1α（PP1α）与真核起始因子2α（eIF2α）之间相互作用的作用。这种相互作用促进了PP1α的eIF2α去磷酸化，抑制SG形成。NS2B-PP1α复合物表现出显著的稳定性，抵抗泛素诱导的降解并放大eIF2α去磷酸化，从而促进ZIKV复制。相比之下,NS2BV35A突变体,仅与eIF2α相互作用，无法抑制SG形成，导致病毒复制减少和对脑类器官生长的影响减弱。这些发现揭示了PP1α在ZIKV感染中的双重作用，诱导干扰素产生作为抗病毒因子和抑制SG形成作为病毒启动子。此外，我们发现，NS2B也作为一个通用的机制采用黄病毒来对抗宿主抗病毒防御，主要通过广泛抑制SG的形成。这项研究促进了我们对黄病毒与宿主相互作用中复杂相互作用的理解，为抗黄病毒感染的创新治疗策略提供了潜力。
