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.

除了研究严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的病毒学外，发现宿主-病毒依赖性对于确定和设计有效的抗病毒治疗策略至关重要。在这里，我们报告了 SARS-CoV-2 进入受体 ACE2 与小泛素样修饰物 3 (SUMO3) 结合，并提供证据表明预防 ACE2 SUMO 化可以阻止 SARS-CoV-2 感染。E3 SUMO 连接酶 PIAS4 促进 ACE2 的 SUMO 化和稳定化，而去 SUMO 化酶 SENP3 逆转这一过程。SUMO3 与 ACE2 在赖氨酸 (K) 187 处的结合会阻碍 ACE2 的 K48 泛素化，从而抑制其随后的货物受体 TOLLIP 依赖​​性自噬降解。托利普缺乏导致 ACE2 稳定和 SARS-CoV-2 感染升高。总之，我们的研究结果表明，由 SUMO 化和泛素化精心策划的 ACE2 选择性自噬降解是对抗 SARS-CoV-2 感染的潜在方法。