National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, China.
Autophagy. 2023 Feb;19(2):737-738. doi: 10.1080/15548627.2022.2103783. Epub 2022 Jul 28.
Upon entering host cells, β-coronaviruses specifically induce generation of replication organelles (ROs) from the endoplasmic reticulum (ER) through their nonstructural protein 3 (nsp3) and nsp4 for viral genome transcription and replication. The most predominant ROs are double-membrane vesicles (DMVs). The ER-resident proteins VMP1 and TMEM41B, which form a complex to regulate autophagosome and lipid droplet (LD) formation, were recently shown to be essential for β-coronavirus infection. Here we report that VMP1 and TMEM41B contribute to DMV generation but function at different steps. TMEM41B facilitates nsp3-nsp4 interaction and ER zippering, while VMP1 is required for subsequent closing of the paired ER into DMVs. Additionally, inhibition of phosphatidylserine (PS) formation by partially reverses the DMV and LD defects in KO cells, suggesting that appropriate PS levels also contribute to DMV formation. This work provides clues to the mechanism of how host proteins collaborate with viral proteins for endomembrane reshaping to promote viral infection.
进入宿主细胞后，β 冠状病毒通过其非结构蛋白 3（nsp3）和 nsp4 特异性地上调内质网（ER）生成复制细胞器（RO），用于病毒基因组转录和复制。最主要的 RO 是双膜囊泡（DMVs）。最近发现，驻留在 ER 中的蛋白质 VMP1 和 TMEM41B 形成复合物以调节自噬体和脂滴（LD）的形成，这对于 β 冠状病毒感染是必不可少的。在这里，我们报告 VMP1 和 TMEM41B 有助于 DMV 的产生，但作用于不同的步骤。TMEM41B 促进 nsp3-nsp4 相互作用和 ER 拉链，而 VMP1 则是随后将配对的 ER 封闭成 DMVs 所必需的。此外，通过部分抑制磷脂酰丝氨酸（PS）的形成，可部分逆转 KO 细胞中的 DMV 和 LD 缺陷，表明适当的 PS 水平也有助于 DMV 的形成。这项工作为宿主蛋白与病毒蛋白如何合作重塑内膜以促进病毒感染的机制提供了线索。
