Am J Respir Cell Mol Biol . Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2

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Am J Respir Cell Mol Biol


. 2023 Feb 2.
doi: 10.1165/rcmb.2022-0331OC. Online ahead of print.
Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2


Joseph S Bednash ¹ , Finny Johns ² , Daniela Farkas ³ , Ajit Elhance ⁴ , Jessica Adair ² , Kirstin Cress ² , Jacob S Yount ⁵ , Adam D Kenney ⁵ , James D Londino ² , Rama K Mallampalli ²



Affiliations

• PMID: 36730646
• DOI: 10.1165/rcmb.2022-0331OC

Abstract

COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) remains a significant public health burden with limited treatment options. Many beta-coronaviruses, including SARS-CoV-2, gain entry to host cells through interaction of SARS-CoV-2 Spike (S) protein with membrane-bound angiotensin-converting enzyme 2 (ACE2). Given its necessity for SARS-CoV-2 infection, ACE2 represents a potential therapeutic target in COVID-19. However, early attempts focusing on ACE2 in COVID-19 have not validated it as a druggable target nor identified other ACE2-related novel proteins for therapeutic intervention. Here, we identify a mechanism for ACE2 protein modulation by the deubiquitinase (DUB) enzyme, ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1). ACE2 is constitutively ubiquitinated and degraded by the proteasome in lung epithelia. SARS-CoV-2 spike protein cellular internalization increased ACE2 protein abundance by decreasing its degradation. Using an siRNA library targeting 96 human DUBs, we identified UCHL1 as a putative regulator of ACE2 function as a viral receptor. Overexpressed UCHL1 preserved ACE2 protein abundance, whereas silencing of the DUB in cells destabilized ACE2 through increased polyubiquitination. A commercially available small molecule inhibitor of UCHL1 DUB activity decreased ACE2 protein levels coupled with inhibition of SARS-CoV-2 infection in epithelial cells. These findings describe a unique pathway of ACE2 regulation uncovering UCHL1 as a potential therapeutic target to modulate COVID-19 viral entry as a platform for future small molecule design and testing. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords: ACE2; COVID-19; SARS-CoV-2; deubiquitinases; ubiquitin.