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

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, Ke Peng, Jincun Zhao and Jun Cui ()
Additional contact information
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

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32957-y

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