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Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2
Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a significant public health burden with limited treatment options. Many β-coronaviruses, including SARS-CoV-2, gain entry to host cells through the interaction of SARS-CoV-2 spike protein...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Thoracic Society
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10174169/ https://www.ncbi.nlm.nih.gov/pubmed/36730646 http://dx.doi.org/10.1165/rcmb.2022-0331OC |
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author | Bednash, Joseph S. Johns, Finny Farkas, Daniela Elhance, Ajit Adair, Jessica Cress, Kirstin Yount, Jacob S. Kenney, Adam D. Londino, James D. Mallampalli, Rama K. |
author_facet | Bednash, Joseph S. Johns, Finny Farkas, Daniela Elhance, Ajit Adair, Jessica Cress, Kirstin Yount, Jacob S. Kenney, Adam D. Londino, James D. Mallampalli, Rama K. |
author_sort | Bednash, Joseph S. |
collection | PubMed |
description | Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a significant public health burden with limited treatment options. Many β-coronaviruses, including SARS-CoV-2, gain entry to host cells through the interaction of SARS-CoV-2 spike protein with membrane-bound ACE2 (angiotensin-converting enzyme 2). 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 UCHL1 (ubiquitin carboxyl-terminal hydrolase isozyme L1). 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 concentrations 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. |
format | Online Article Text |
id | pubmed-10174169 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Thoracic Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-101741692023-05-12 Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2 Bednash, Joseph S. Johns, Finny Farkas, Daniela Elhance, Ajit Adair, Jessica Cress, Kirstin Yount, Jacob S. Kenney, Adam D. Londino, James D. Mallampalli, Rama K. Am J Respir Cell Mol Biol Original Research Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a significant public health burden with limited treatment options. Many β-coronaviruses, including SARS-CoV-2, gain entry to host cells through the interaction of SARS-CoV-2 spike protein with membrane-bound ACE2 (angiotensin-converting enzyme 2). 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 UCHL1 (ubiquitin carboxyl-terminal hydrolase isozyme L1). 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 concentrations 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. American Thoracic Society 2023-02-02 /pmc/articles/PMC10174169/ /pubmed/36730646 http://dx.doi.org/10.1165/rcmb.2022-0331OC Text en Copyright © 2023 by the American Thoracic Society https://creativecommons.org/licenses/by-nc-nd/4.0/This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) . For commercial usage and reprints, please e-mail Diane Gern. |
spellingShingle | Original Research Bednash, Joseph S. Johns, Finny Farkas, Daniela Elhance, Ajit Adair, Jessica Cress, Kirstin Yount, Jacob S. Kenney, Adam D. Londino, James D. Mallampalli, Rama K. Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2 |
title | Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2 |
title_full | Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2 |
title_fullStr | Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2 |
title_full_unstemmed | Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2 |
title_short | Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2 |
title_sort | inhibiting the deubiquitinase uchl1 reduces sars-cov-2 viral uptake by ace2 |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10174169/ https://www.ncbi.nlm.nih.gov/pubmed/36730646 http://dx.doi.org/10.1165/rcmb.2022-0331OC |
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