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

• Published in: Nature communications Vol. 13; no. 1; p. 5204
• Main Authors: Jin, Shouheng, He, Xing, Ma, Ling, Zhuang, Zhen, Wang, Yiliang, Lin, Meng, Cai, Sihui, Wei, Lu, Wang, Zheyu, Zhao, Zhiyao, Wu, Yaoxing, Sun, Lin, Li, Chunwei, Xie, Weihong, Zhao, Yong, Songyang, Zhou, Peng, Ke, Zhao, Jincun, Cui, Jun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 14/63; 38/109; 38/77; 38/88; 38/89; 631/326/596/2557; 631/326/596/4130; 631/337/458/538; 631/80/39; 82/58; 82/80; 96/1; 96/44; 96/95; ACE2; Angiotensin-Converting Enzyme 2; Antiviral agents; Autophagy; Conjugation; Coronaviruses; COVID-19; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; Degradation; Humanities and Social Sciences; Humans; Infections; Intracellular Signaling Peptides and Proteins - metabolism; Lysine; multidisciplinary; Receptors; Respiratory diseases; SARS-CoV-2; Science; Science (multidisciplinary); Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - metabolism; Stabilization; SUMO protein; Sumoylation; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Viral diseases; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32957-y

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. SARS- CoV-2 hijacks ACE2 for cell entry. Here, the authors report that dynamic SUMOylation modulates the TOLLIP-directed selective autophagic degradation of ACE2 and suggest SUMOylation inhibition as a potential intervention against SARS-CoV-2 infection.