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Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor
Nature Genetics ( IF 31.7 ) Pub Date : 2020-10-19 , DOI: 10.1038/s41588-020-00731-9
Olusegun O Onabajo 1 , A Rouf Banday 1 , Megan L Stanifer 2 , Wusheng Yan 1 , Adeola Obajemu 1 , Deanna M Santer 3 , Oscar Florez-Vargas 1 , Helen Piontkivska 4 , Joselin M Vargas 1 , Timothy J Ring 1 , Carmon Kee 5, 6 , Patricio Doldan 5, 6 , D Lorne Tyrrell 3 , Juan L Mendoza 7 , Steeve Boulant 5, 6 , Ludmila Prokunina-Olsson 1
Affiliation  

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, utilizes angiotensin-converting enzyme 2 (ACE2) for entry into target cells. ACE2 has been proposed as an interferon-stimulated gene (ISG). Thus, interferon-induced variability in ACE2 expression levels could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a novel, transcriptionally independent truncated isoform of ACE2, which we designate as deltaACE2 (dACE2). We demonstrate that dACE2, but not ACE2, is an ISG. In The Cancer Genome Atlas, the expression of dACE2 was enriched in squamous tumors of the respiratory, gastrointestinal and urogenital tracts. In vitro, dACE2, which lacks 356 amino-terminal amino acids, was non-functional in binding the SARS-CoV-2 spike protein and as a carboxypeptidase. Our results suggest that the ISG-type induction of dACE2 in IFN-high conditions created by treatments, an inflammatory tumor microenvironment or viral co-infections is unlikely to increase the cellular entry of SARS-CoV-2 and promote infection.



中文翻译:

干扰素和病毒诱导一种新型截短的 ACE2 亚型,而不是全长 SARS-CoV-2 受体

导致 COVID-19 的严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 利用血管紧张素转换酶 2 (ACE2) 进入靶细胞。ACE2已被提议作为干扰素刺激基因 (ISG)。因此,干扰素诱导的ACE2表达水平变异可能对 COVID-19 或其结果的易感性很重要。在这里,我们报告发现了一种新的、转录独立的ACE2截短异构体,我们将其命名为deltaACE2 ( dACE2 )。我们证明dACE2而非ACE2是 ISG。在癌症基因组图谱中,dACE2的表达在呼吸道、胃肠道和泌尿生殖道的鳞状肿瘤中富集。在体外,缺乏 356 个氨基末端氨基酸的 dACE2 在结合 SARS-CoV-2 刺突蛋白和作为羧肽酶方面是无功能的。我们的研究结果表明,在由治疗、炎症性肿瘤微环境或病毒共同感染产生的高 IFN 条件下, dACE2的 ISG 型诱导不太可能增加 SARS-CoV-2 的细胞进入并促进感染。

更新日期:2020-10-19
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