β-coronaviruses reshape host cell endomembranes to form double-membrane vesicles (DMVs) for genome replication and transcription. Ectopically expressed viral nonstructural proteins nsp3 and nsp4 interact to zipper and bend the ER for DMV biogenesis. Genome-wide screens revealed the autophagy proteins VMP1 and TMEM41B as important host factors for SARS-CoV-2 infection. Here, we demonstrated that DMV biogenesis, induced by virus infection or expression of nsp3/4, is impaired in the VMP1 KO or TMEM41B KO cells. In VMP1 KO cells, the nsp3/4 complex forms normally, but the zippered ER fails to close into DMVs. In TMEM41B KO cells, the nsp3–nsp4 interaction is reduced and DMV formation is suppressed. Thus, VMP1 and TMEM41B function at different steps during DMV formation. VMP1 was shown to regulate cross-membrane phosphatidylserine (PS) distribution. Inhibiting PS synthesis partially rescues the DMV defects in VMP1 KO cells, suggesting that PS participates in DMV formation. We provide molecular insights into the collaboration of host factors with viral proteins to remodel host organelles.
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6 June 2022
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May 10 2022
VMP1 and TMEM41B are essential for DMV formation during β-coronavirus infection
Mingming Ji
,
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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Meng Li
,
2
Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, China
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Long Sun
,
3
CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
4
University of Chinese Academy of Sciences, Beijing, China
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Hongyu Zhao,
Hongyu Zhao
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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Ying Li,
Ying Li
5
Technology Center for Protein Sciences, School of Life Science, Tsinghua University, Beijing, China
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Lulu Zhou,
Lulu Zhou
6
Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China
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Zhenni Yang,
Zhenni Yang
2
Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, China
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Xin Zhao,
Xin Zhao
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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Wenyan Qu,
Wenyan Qu
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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Hanbing Xue,
Hanbing Xue
2
Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, China
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Ze Zheng,
Ze Zheng
2
Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, China
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Yiming Li
,
Yiming Li
6
Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China
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Hongyu Deng,
3
CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
4
University of Chinese Academy of Sciences, Beijing, China
Hongyu Deng: hydeng@moon.ibp.ac.cn
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Yan G. Zhao
2
Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, China
7Brain Research Center, Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, China
Correspondence to Yan G. Zhao: zhaoyan@sustech.edu.cn
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1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
2
Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, China
3
CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
4
University of Chinese Academy of Sciences, Beijing, China
Hongyu Zhao
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
Ying Li
5
Technology Center for Protein Sciences, School of Life Science, Tsinghua University, Beijing, China
Lulu Zhou
6
Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China
Zhenni Yang
2
Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, China
Xin Zhao
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
Wenyan Qu
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
Hanbing Xue
2
Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, China
Ze Zheng
2
Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, China
Yiming Li
6
Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China
3
CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
4
University of Chinese Academy of Sciences, Beijing, China
Correspondence to Yan G. Zhao: zhaoyan@sustech.edu.cn
Hongyu Deng: hydeng@moon.ibp.ac.cn
*
M. Ji, M. Li, and L. Sun contributed equally to this paper.
Received:
December 15 2021
Revision Received:
April 04 2022
Accepted:
April 08 2022
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding
Funder(s):
National Key Research and Development Program of China
- Award Id(s): 2021YFA1300800
Funder(s):
National Natural Science Foundation of China
- Award Id(s): 32170753
Funder(s):
Chinese Academy of Sciences
- Award Id(s): XDB37030205,KJZD-SW-L05
Funder(s):
Shenzhen–Hong Kong Institute of Brain Science–Shenzhen Fundamental Research Institutions
- Award Id(s): 2021SHIBS0002
© 2022 Ji et al.
2022
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2022) 221 (6): e202112081.
Article history
Received:
December 15 2021
Revision Received:
April 04 2022
Accepted:
April 08 2022
Citation
Mingming Ji, Meng Li, Long Sun, Hongyu Zhao, Ying Li, Lulu Zhou, Zhenni Yang, Xin Zhao, Wenyan Qu, Hanbing Xue, Ze Zheng, Yiming Li, Hongyu Deng, Yan G. Zhao; VMP1 and TMEM41B are essential for DMV formation during β-coronavirus infection. J Cell Biol 6 June 2022; 221 (6): e202112081. doi: https://doi.org/10.1083/jcb.202112081
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