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
  • 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. [email protected].
  • 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. [email protected].
  • # Contributed equally.
PMID: 36057605 DOI: 10.1038/s41467-022-32957-y
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.

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