Mitophagy antagonism by ZIKV reveals Ajuba as a regulator of PINK1 signaling, PKR-dependent inflammation, and viral invasion of tissues
Mitophagy antagonism by ZIKV reveals Ajuba as a regulator of PINK1 signaling, PKR-dependent inflammation, and viral invasion of tissues
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ZIKV对线粒体自噬的拮抗作用表明，Ajuba是PINK1信号、pkr依赖性炎症和病毒侵入组织的调节剂
DOI：
10.1016/j.celrep.2021.109888
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发表时间：
2021-10-26
期刊：
影响因子：
8.8
通讯作者：
Best, Sonja M.
中科院分区：
文献类型：
--
作者：
Ponia, Sanket S.;Robertson, Shelly J.;Best, Sonja M.
以趋化因子表达为主的炎症失调是感染全球重要的人类病原体寨卡病毒（ZIKV）和登革热病毒后疾病的一个关键特征，但缺乏对促炎症反应如何启动的机制理解。线粒体自噬是一种质量控制机制，通过选择性降解受损线粒体来调节先天免疫信号和细胞因子的产生。在此，我们证明 ZIKV 非结构蛋白 5 (NS5) 通过与宿主蛋白 Ajuba 结合并防止其易位至去极化线粒体（PINK1 激活和下游信号传导所需）来拮抗线粒体自噬。随后的线粒体自噬抑制通过线粒体 RNA 的蛋白激酶 R (PKR) 感应放大了促炎趋化因子的产生。在 Ajuba(-/-) 小鼠中，ZIKV 诱导促炎趋化因子的早期表达，并显着增强向组织的传播。这项工作将 Ajuba 确定为线粒体自噬的关键调节因子，并证明线粒体自噬在限制全球重要人类病毒感染后的全身炎症中的作用。
Dysregulated inflammation dominated by chemokine expression is a key feature of disease following infection with the globally important human pathogens Zika virus (ZIKV) and dengue virus, but a mechanistic understanding of how pro-inflammatory responses are initiated is lacking. Mitophagy is a quality-control mechanism that regulates innate immune signaling and cytokine production through selective degradation of damaged mitochondria. Here, we demonstrate that ZIKV nonstructural protein 5 (NS5) antagonizes mitophagy by binding to the host protein Ajuba and preventing its translocation to depolarized mitochondria where it is required for PINK1 activation and downstream signaling. Consequent mitophagy suppression amplifies the production of pro-inflammatory chemokines through protein kinase R (PKR) sensing of mitochondrial RNA. In Ajuba(-/-) mice, ZIKV induces early expression of pro-inflammatory chemokines associated with significantly enhanced dissemination to tissues. This work identifies Ajuba as a critical regulator of mitophagy and demonstrates a role for mitophagy in limiting systemic inflammation following infection by globally important human viruses.