Zhang Linliang, Qin Yali, Chen Mingzhou
Centre for Virology and Vaccine Research, School of Life Sciences, Hubei University, Wuhan, China.
Autophagy. 2025 May;21(5):1167-1168. doi: 10.1080/15548627.2025.2457112. Epub 2025 Feb 7.
Selective endoplasmic reticulum (ER) autophagy (reticulophagy) is essential for maintaining ER homeostasis. The E3 ligase AMFR facilitates the ubiquitination of the reticulophagy receptor RETREG1/FAM134B, thereby promoting the dynamic flux of the reticulophagy process. Flaviviruses exploit the ER during their replication cycles, highlighting the importance of ER quantity and accessibility in flavivirus infections. However, the role of reticulophagy in viral replication and the complex mechanisms by which viruses modulate reticulophagy to enhance pathogenicity remain poorly understood. In a recent study, we demonstrate that the Zika virus (ZIKV) hijacks the ER-located E3 ligase AMFR to ubiquitinate NS2A, leading to the degradation of the key reticulophagy receptor RETREG1. This inhibition of the reticulophagy process promotes virus-induced microcephaly in human brain organoids and enhances viral pathogenicity in mouse models. Notably, the AMFR-mediated ubiquitination of ZIKV-NS2A and its functional interaction with RETREG1 are conserved across the NS2A of other flaviviruses, including those from Dengue virus, West Nile virus, and Japanese encephalitis virus.
选择性内质网（ER）自噬（网织自噬）对于维持内质网稳态至关重要。E3连接酶AMFR促进网织自噬受体RETREG1/FAM134B的泛素化，从而促进网织自噬过程的动态通量。黄病毒在其复制周期中利用内质网，突出了内质网数量和可及性在黄病毒感染中的重要性。然而，网织自噬在病毒复制中的作用以及病毒调节网织自噬以增强致病性的复杂机制仍知之甚少。在最近的一项研究中，我们证明寨卡病毒（ZIKV）劫持位于内质网的E3连接酶AMFR来泛素化NS2A，导致关键的网织自噬受体RETREG1降解。这种对网织自噬过程的抑制促进了人脑海绵体中病毒诱导的小头畸形，并增强了小鼠模型中的病毒致病性。值得注意的是，AMFR介导的ZIKV-NS2A泛素化及其与RETREG1的功能相互作用在其他黄病毒的NS2A中是保守的，包括登革病毒、西尼罗河病毒和日本脑炎病毒。
