Role of Human Antigen R (HuR) in the Regulation of Pulmonary ACE2 Expression.

Noof Aloufi,Sergio Di Marco,Carolyn J Baglole,Imed-Eddine Gallouzi,David H Eidelman,Zahraa Haidar,Sabah N Hussain,Parameswaran Nair,Andrea Benedetti,Jun Ding

doi:10.3390/cells11010022

Abstract

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 ELAVL1 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 ELAVL1 and ACE2 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 ACE2 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.

Highlights

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide [1]
We used human lung fibroblasts (HLFs) to mechanistically evaluate the involvement of human antigen R (HuR) in controlling angiotensin-converting enzyme 2 (ACE2) expression, as we have previously shown that HuR protein is constitutively expressed in these cells [28] and that there is more ACE2 protein in COPD-derived lung fibroblasts [9]
COPD patients may be at risk of increased hospitalization and severe illness from COVID-19 caused by SARS-CoV-2 [5]

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide [1]. COPD is the third leading cause of death [2], which is expected to further increase in the coming decades. COVID-19 has rapidly spread through the world and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel β-coronavirus [6]. One reason that individuals with COPD may be at heightened risk for severe COVID-19 is the increased expression of the angiotensin-converting enzyme 2 (ACE2), the entry receptor for SARS-CoV-2 [6,7]. ACE2 is the primary means for SARS-CoV-2 entry, maintenance of ACE2 levels is essential for combatting inflammatory and fibrotic lung disease [13]. Ang-(1-7) activates the Mas receptor, leading to release of nitric oxide, prostaglandin E2, and bradykinin [15], resulting in vasodilation, natriuresis and a decrease in inflammation [16,17]

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Conclusion