Identifying binding partners, biological substrates and antisense oligonucleotides regulating expression of short and long ACE2.

ACE2是SARS-CoV-2的主要病毒入口点。我们和其他人最近证明了两种形式的ACE2，短和长，在气道上皮细胞中表达，并且它们的表达受独立启动子的控制，短ACE2被IFN强烈诱导。两者在鼻病毒感染时均上调，但在SARS-CoV-2感染时则不上调。短ACE2缺乏SARS-CoV-2刺突结合的高亲和力结合残基，提示其不具备SARS-CoV-2结合能力。初步研究表明，短ACE2比长ACE2更不稳定。短ACE2具有跨膜结构域，但没有信号肽，短ACE2是否位于膜内以及其转运机制尚不清楚。作为一种新发现的分子，人们对短链ACE2的生理功能及其在SARS-CoV-2感染中的作用知之甚少。在本项目中，我们旨在确定ACE2的短和长结合伙伴和生物学底物，并研究用反义寡核苷酸调节ACE2的短和长表达是否可以改变呼吸上皮细胞模型中SARS-CoV-2的感染性。

ACE2 is the main viral entry point for SARS-CoV-2. We and others have recently demonstrated that two forms of ACE2, short and long, are expressed in airway epithelial cells, and that expression of these is under the control of independent promoters, with short ACE2 being strongly induced by IFN. Both are upregulated in response to rhinovirus infection but not SARS-CoV-2 infection.Short ACE2 lacks the high affinity binding residues for SARS-CoV-2 spike binding, suggesting that it is not capable of SARS-CoV-2 binding. Preliminary work suggests that short ACE2 is less stable than long ACE2. Short ACE2 has a transmembrane domain but no signal peptide, and it remains unclear whether short ACE2 is located in the membrane and the mechanism of transport of ACE2. As a recently discovered molecule, little is understood about the physiological function of short ACE2 and its role in SARS-CoV-2 infectivity. In this project we aim to identify the binding partners and biological substrates of short and long ACE2 and investigate whether modulation of expression of short and long ACE2 with antisense olignucleotides can modify SARS-CoV-2 infectivity in cell models of respiratory epithelium.