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A genome-wide CRISPR screen identifies host factors that regulate SARS-CoV-2 entry

Author

Listed:
  • Yunkai Zhu

    (Fudan University)

  • Fei Feng

    (Fudan University)

  • Gaowei Hu

    (Fudan University)

  • Yuyan Wang

    (Fudan University)

  • Yin Yu

    (Fudan University)

  • Yuanfei Zhu

    (Fudan University)

  • Wei Xu

    (Fudan University)

  • Xia Cai

    (Fudan University)

  • Zhiping Sun

    (Fudan University)

  • Wendong Han

    (Fudan University)

  • Rong Ye

    (Fudan University)

  • Di Qu

    (Fudan University)

  • Qiang Ding

    (Tsinghua University)

  • Xinxin Huang

    (Plant and Food Inspection and Quarantine of Shanghai Customs)

  • Hongjun Chen

    (CAAS)

  • Wei Xu

    (Southern Medical University)

  • Youhua Xie

    (Fudan University)

  • Qiliang Cai

    (Fudan University)

  • Zhenghong Yuan

    (Fudan University)

  • Rong Zhang

    (Fudan University)

Abstract

The global spread of SARS-CoV-2 is posing major public health challenges. One feature of SARS-CoV-2 spike protein is the insertion of multi-basic residues at the S1/S2 subunit cleavage site. Here, we find that the virus with intact spike (Sfull) preferentially enters cells via fusion at the plasma membrane, whereas a clone (Sdel) with deletion disrupting the multi-basic S1/S2 site utilizes an endosomal entry pathway. Using Sdel as model, we perform a genome-wide CRISPR screen and identify several endosomal entry-specific regulators. Experimental validation of hits from the CRISPR screen shows that host factors regulating the surface expression of angiotensin-converting enzyme 2 (ACE2) affect entry of Sfull virus. Animal-to-animal transmission with the Sdel virus is reduced compared to Sfull in the hamster model. These findings highlight the critical role of the S1/S2 boundary of SARS-CoV-2 spike protein in modulating virus entry and transmission and provide insights into entry of coronaviruses.

Suggested Citation

  • Yunkai Zhu & Fei Feng & Gaowei Hu & Yuyan Wang & Yin Yu & Yuanfei Zhu & Wei Xu & Xia Cai & Zhiping Sun & Wendong Han & Rong Ye & Di Qu & Qiang Ding & Xinxin Huang & Hongjun Chen & Wei Xu & Youhua Xie , 2021. "A genome-wide CRISPR screen identifies host factors that regulate SARS-CoV-2 entry," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21213-4
    DOI: 10.1038/s41467-021-21213-4
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    Cited by:

    1. Jiakai Hou & Yanjun Wei & Jing Zou & Roshni Jaffery & Long Sun & Shaoheng Liang & Ningbo Zheng & Ashley M. Guerrero & Nicholas A. Egan & Ritu Bohat & Si Chen & Caishang Zheng & Xiaobo Mao & S. Stephen, 2024. "Integrated multi-omics analyses identify anti-viral host factors and pathways controlling SARS-CoV-2 infection," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Joseph D. Trimarco & Sarah L. Nelson & Ryan R. Chaparian & Alexandra I. Wells & Nathan B. Murray & Parastoo Azadi & Carolyn B. Coyne & Nicholas S. Heaton, 2022. "Cellular glycan modification by B3GAT1 broadly restricts influenza virus infection," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Rebeka Butkovič & Alexander P. Walker & Michael D. Healy & Kerrie E. McNally & Meihan Liu & Tineke Veenendaal & Kohji Kato & Nalan Liv & Judith Klumperman & Brett M. Collins & Peter J. Cullen, 2024. "Mechanism and regulation of cargo entry into the Commander endosomal recycling pathway," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Ma’ayan Israeli & Yaara Finkel & Yfat Yahalom-Ronen & Nir Paran & Theodor Chitlaru & Ofir Israeli & Inbar Cohen-Gihon & Moshe Aftalion & Reut Falach & Shahar Rotem & Uri Elia & Ital Nemet & Limor Klik, 2022. "Genome-wide CRISPR screens identify GATA6 as a proviral host factor for SARS-CoV-2 via modulation of ACE2," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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