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

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

  • Nat Commun. 2022 Sep 3;13(1):5204. doi: 10.1038/s41467-022-32957-y.
Shouheng Jin  # 1 Xing He  # 2 Ling Ma 2 Zhen Zhuang 3 Yiliang Wang 3 Meng Lin 2 Sihui Cai 2 Lu Wei 2 Zheyu Wang 2 Zhiyao Zhao 3 Yaoxing Wu 2 Lin Sun 4 Chunwei Li 4 Weihong Xie 2 Yong Zhao 2 Zhou Songyang 2 Ke Peng 5 Jincun Zhao 3 Jun Cui 6
Affiliations

Affiliations

  • 1 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, 510275, Guangzhou, Guangdong, China. jinshh3@mail.sysu.edu.cn.
  • 2 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, 510275, Guangzhou, Guangdong, China.
  • 3 State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, 510182, Guangzhou, Guangdong, China.
  • 4 Department of Otolaryngology, First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China.
  • 5 State Key Laboratory of Virology, CAS Key Laboratory of Special Pathogens, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, Hubei, China.
  • 6 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, 510275, Guangzhou, Guangdong, China. cuij5@mail.sysu.edu.cn.
  • # Contributed equally.
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.

Figures
Products