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

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


    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

    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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