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

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^*

Source：Nature Communications, 2022, 13(1): 5204.

DOI：10.1038/s41467-022-32957-y

• VIRUS
• SUMO
• PATHWAY
• ENTRY
• INTERFERON
• CELLS
• DEGRADATION
• PROTEINS
• COVID-19
• RECEPTOR

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. @@@ 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.

• Institution
  中山大学; 1; 广州医学院; 中国科学院