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Suppression of ACE2 SUMOylation protects against SARS-CoV-2 infection through TOLLIP-mediated selective autophagy

Author

Listed:
  • Shouheng Jin

    (Sun Yat-sen University)

  • Xing He

    (Sun Yat-sen University)

  • Ling Ma

    (Sun Yat-sen University)

  • Zhen Zhuang

    (The First Affiliated Hospital of Guangzhou Medical University)

  • Yiliang Wang

    (The First Affiliated Hospital of Guangzhou Medical University)

  • Meng Lin

    (Sun Yat-sen University)

  • Sihui Cai

    (Sun Yat-sen University)

  • Lu Wei

    (Sun Yat-sen University)

  • Zheyu Wang

    (Sun Yat-sen University)

  • Zhiyao Zhao

    (The First Affiliated Hospital of Guangzhou Medical University)

  • Yaoxing Wu

    (Sun Yat-sen University)

  • Lin Sun

    (Sun Yat-sen University)

  • Chunwei Li

    (Sun Yat-sen University)

  • Weihong Xie

    (Sun Yat-sen University)

  • Yong Zhao

    (Sun Yat-sen University)

  • Zhou Songyang

    (Sun Yat-sen University)

  • Ke Peng

    (Chinese Academy of Sciences)

  • Jincun Zhao

    (The First Affiliated Hospital of Guangzhou Medical University)

  • Jun Cui

    (Sun Yat-sen University)

Abstract

In addition to investigating the virology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), discovering the host–virus dependencies are essential to identify and design effective antiviral therapy strategy. Here, we report that the SARS-CoV-2 entry receptor, ACE2, conjugates with small ubiquitin-like modifier 3 (SUMO3) and provide evidence indicating that prevention of ACE2 SUMOylation can block SARS-CoV-2 infection. E3 SUMO ligase PIAS4 prompts the SUMOylation and stabilization of ACE2, whereas deSUMOylation enzyme SENP3 reverses this process. Conjugation of SUMO3 with ACE2 at lysine (K) 187 hampers the K48-linked ubiquitination of ACE2, thus suppressing its subsequent cargo receptor TOLLIP-dependent autophagic degradation. TOLLIP deficiency results in the stabilization of ACE2 and elevated SARS-CoV-2 infection. In conclusion, our findings suggest selective autophagic degradation of ACE2 orchestrated by SUMOylation and ubiquitination as a potential way to combat SARS-CoV-2 infection.

Suggested Citation

  • Shouheng Jin & Xing He & Ling Ma & Zhen Zhuang & Yiliang Wang & Meng Lin & Sihui Cai & Lu Wei & Zheyu Wang & Zhiyao Zhao & Yaoxing Wu & Lin Sun & Chunwei Li & Weihong Xie & Yong Zhao & Zhou Songyang &, 2022. "Suppression of ACE2 SUMOylation protects against SARS-CoV-2 infection through TOLLIP-mediated selective autophagy," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32957-y
    DOI: 10.1038/s41467-022-32957-y
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