Tu Wen Juan, McCuaig Robert D, Melino Michelle, Rawle Daniel J, Le Thuy T, Yan Kexin, Suhrbier Andreas, Johnston Rebecca L, Koufariotis Lambros T, Waddell Nicola, Cross Emily M, Tsimbalyuk Sofiya, Bain Amanda, Ahern Elizabeth, Collinson Natasha, Phipps Simon, Forwood Jade K, Seddiki Nabila, Rao Sudha
Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
The Inflammation Biology Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Cell Discov. 2021 May 24;7(1):37. doi: 10.1038/s41421-021-00279-w.
Treatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus-ACE2 interactions. Two newly developed peptide inhibitors competitively inhibited virus-ACE2 interactions, and demethylase access to significantly inhibit viral replication. Similar to some other predominantly plasma membrane proteins, ACE2 had a novel nuclear function: its cytoplasmic domain harbors a nuclear shuttling domain, which when demethylated by LSD1 promoted importin-α-dependent nuclear ACE2 entry following infection to regulate active transcription. A novel, cell permeable ACE2 peptide inhibitor prevented ACE2 nuclear entry, significantly inhibiting viral replication in SARS-CoV-2-infected cell lines, outperforming other LSD1 inhibitors. These data raise the prospect of post-exposure prophylaxis for SARS-CoV-2, either through repurposed LSD1 inhibitors or new, nuclear-specific ACE2 inhibitors.
新型冠状病毒肺炎（COVID-19）的治疗选择仍然有限，尤其是在早期或无症状阶段。在此，我们报告了一种由血管紧张素转换酶2（ACE2）与表观遗传擦除酶赖氨酸特异性去甲基化酶1（LSD1）之间的相互作用介导的新型严重急性呼吸综合征冠状病毒2（SARS-CoV-2）病毒复制机制，以及它与核穿梭输入蛋白途径的相互作用。最近的研究表明输入蛋白途径在SARS-CoV-2感染中起关键作用，许多RNA病毒劫持该轴来重新定向宿主细胞转录。LSD1在细胞表面与ACE2共定位，以维持SARS-CoV-2刺突受体结合域赖氨酸31的去甲基化，从而促进病毒与ACE2的相互作用。两种新开发的肽抑制剂竞争性抑制病毒与ACE2的相互作用，并抑制去甲基化酶的活性，从而显著抑制病毒复制。与其他一些主要位于质膜的蛋白质类似，ACE2具有一种新的核功能：其胞质结构域含有一个核穿梭结构域，在感染后被LSD1去甲基化时，可促进依赖输入蛋白α的核ACE2进入，从而调节活性转录。一种新型的、可穿透细胞的ACE2肽抑制剂可阻止ACE2进入细胞核，显著抑制SARS-CoV-2感染的细胞系中的病毒复制，其效果优于其他LSD1抑制剂。这些数据为通过重新利用LSD1抑制剂或新型核特异性ACE2抑制剂对SARS-CoV-2进行暴露后预防带来了希望。
