DMV biogenesis during β-coronavirus infection requires autophagy proteins VMP1 and TMEM41B

Autophagy. 2023 Feb;19(2):737-738. doi: 10.1080/15548627.2022.2103783. Epub 2022 Jul 28.

Abstract

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 siPTDSS1 partially reverses the DMV and LD defects in VMP1 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.

Keywords: DMV; TMEM41B; VMP1; nsp3; nsp4; Β-coronavirus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy
  • Coronavirus Infections*
  • Coronavirus*
  • Endoplasmic Reticulum
  • Membrane Proteins
  • Reactive Oxygen Species
  • Virus Replication

Substances

  • Membrane Proteins
  • Reactive Oxygen Species

Grants and funding

This work was supported by Chinese Ministry of Science and Technology of the People’s Republic of China [National Key Research and Development Program, 2021YFA1300802 to Y.G.Z. and H.D.], the National Natural Science Foundation of China (NSFC) [32170753 to Y.G.Z.], the Chinese Academy of Sciences [XDB37030205 and KJZD-SW-L05 to H.D.], and the Shenzhen–Hong Kong Institute of Brain Science–Shenzhen Fundamental Research Institutions [2022SHIBS0002 to Y.G.Z.].