Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, QC H4A 3J1, Canada.
Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Cells. 2021 Dec 22;11(1):22. doi: 10.3390/cells11010022.
Patients with COPD may be at an increased risk for severe illness from COVID-19 because of ACE2 upregulation, the entry receptor for SARS-CoV-2. Chronic exposure to cigarette smoke, the main risk factor for COPD, increases pulmonary ACE2. How ACE2 expression is controlled is not known but may involve HuR, an RNA binding protein that increases protein expression by stabilizing mRNA. We hypothesized that HuR would increase ACE2 protein expression. We analyzed scRNA-seq data to profile expression in distinct respiratory cell populations in COVID-19 and COPD patients. HuR expression and cellular localization was evaluated in COPD lung tissue by multiplex immunohistochemistry and in human lung cells by imaging flow cytometry. The regulation of ACE2 expression was evaluated using siRNA-mediated knockdown of HuR. There is a significant positive correlation between and in COPD cells. HuR cytoplasmic localization is higher in smoker and COPD lung tissue; there were also higher levels of cleaved HuR (CP-1). HuR binds to mRNA but knockdown of HuR does not change ACE2 protein levels in primary human lung fibroblasts (HLFs). Our work is the first to investigate the association between ACE2 and HuR. Further investigation is needed to understand the mechanistic underpinning behind the regulation of ACE2 expression.
慢性阻塞性肺疾病（COPD）患者由于 ACE2 的上调而可能面临 COVID-19 严重疾病的风险增加，ACE2 是 SARS-CoV-2 的进入受体。慢性暴露于香烟烟雾是 COPD 的主要危险因素，会增加肺部 ACE2。ACE2 表达的控制方式尚不清楚，但可能涉及 RNA 结合蛋白 HuR，它通过稳定 mRNA 来增加蛋白表达。我们假设 HuR 会增加 ACE2 蛋白的表达。我们分析了 scRNA-seq 数据，以分析 COVID-19 和 COPD 患者不同呼吸细胞群中的表达情况。通过多重免疫荧光和成像流式细胞术评估 COPD 肺组织中 HuR 的表达和细胞定位，以及人肺细胞中的 HuR。通过 HuR 的 siRNA 介导的敲低来评估 ACE2 表达的调控。在 COPD 细胞中，与 ACE2 呈显著正相关。在吸烟者和 COPD 肺组织中，HuR 的细胞质定位较高；也有较高水平的裂解 HuR（CP-1）。HuR 与 mRNA 结合，但敲低 HuR 不会改变原代人肺成纤维细胞（HLFs）中的 ACE2 蛋白水平。我们的工作是首次研究 ACE2 和 HuR 之间的关联。需要进一步研究以了解 ACE2 表达调控背后的机制基础。
