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Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreases Viral Load

Despite extensive efforts, COVID-19 pandemic caused by the SARS-CoV-2 virus is still at large. Vaccination is an effective approach to curb virus spread, but several variants (e.g., delta, delta plus, omicron, and IHU) appear to weaken or possibly escape immune protection. Thus, novel and quickly sc...

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Autores principales: Maimaitiyiming, Yasen, Yang, Tao, Wang, Qian Qian, Feng, Yan, Chen, Zhi, Björklund, Mikael, Wang, Fudi, Hu, Chonggao, Hsu, Chih-Hung, Naranmandura, Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AAAS 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8918953/
https://www.ncbi.nlm.nih.gov/pubmed/35321260
http://dx.doi.org/10.34133/2022/9802969
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author Maimaitiyiming, Yasen
Yang, Tao
Wang, Qian Qian
Feng, Yan
Chen, Zhi
Björklund, Mikael
Wang, Fudi
Hu, Chonggao
Hsu, Chih-Hung
Naranmandura, Hua
author_facet Maimaitiyiming, Yasen
Yang, Tao
Wang, Qian Qian
Feng, Yan
Chen, Zhi
Björklund, Mikael
Wang, Fudi
Hu, Chonggao
Hsu, Chih-Hung
Naranmandura, Hua
author_sort Maimaitiyiming, Yasen
collection PubMed
description Despite extensive efforts, COVID-19 pandemic caused by the SARS-CoV-2 virus is still at large. Vaccination is an effective approach to curb virus spread, but several variants (e.g., delta, delta plus, omicron, and IHU) appear to weaken or possibly escape immune protection. Thus, novel and quickly scalable approaches to restrain SARS-CoV-2 are urgently needed. Multiple evidences showed thermal sensitivity of SARS-CoV-2 and negative correlation between environmental temperature and COVID-19 transmission with unknown mechanism. Here, we reveal a potential mechanism by which mild heat treatment destabilizes the wild-type RNA-dependent RNA polymerase (also known as nonstructural protein 12 (NSP12)) of SARS-CoV-2 as well as the P323L mutant commonly found in SARS-CoV-2 variants, including omicron and IHU. Mechanistically, heat treatment promotes E3 ubiquitin ligase ZNF598-dependent NSP12 ubiquitination leading to proteasomal degradation and significantly decreases SARS-CoV-2 RNA copy number and viral titer. A mild daily heat treatment maintains low levels of both wild-type and P323L mutant of NSP12, suggesting clinical potential. Collectively, this novel mechanism, heat-induced NSP12 degradation, suggests a prospective heat-based intervention against SARS-CoV-2.
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spelling pubmed-89189532022-03-22 Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreases Viral Load Maimaitiyiming, Yasen Yang, Tao Wang, Qian Qian Feng, Yan Chen, Zhi Björklund, Mikael Wang, Fudi Hu, Chonggao Hsu, Chih-Hung Naranmandura, Hua Research (Wash D C) Perspective Despite extensive efforts, COVID-19 pandemic caused by the SARS-CoV-2 virus is still at large. Vaccination is an effective approach to curb virus spread, but several variants (e.g., delta, delta plus, omicron, and IHU) appear to weaken or possibly escape immune protection. Thus, novel and quickly scalable approaches to restrain SARS-CoV-2 are urgently needed. Multiple evidences showed thermal sensitivity of SARS-CoV-2 and negative correlation between environmental temperature and COVID-19 transmission with unknown mechanism. Here, we reveal a potential mechanism by which mild heat treatment destabilizes the wild-type RNA-dependent RNA polymerase (also known as nonstructural protein 12 (NSP12)) of SARS-CoV-2 as well as the P323L mutant commonly found in SARS-CoV-2 variants, including omicron and IHU. Mechanistically, heat treatment promotes E3 ubiquitin ligase ZNF598-dependent NSP12 ubiquitination leading to proteasomal degradation and significantly decreases SARS-CoV-2 RNA copy number and viral titer. A mild daily heat treatment maintains low levels of both wild-type and P323L mutant of NSP12, suggesting clinical potential. Collectively, this novel mechanism, heat-induced NSP12 degradation, suggests a prospective heat-based intervention against SARS-CoV-2. AAAS 2022-02-23 /pmc/articles/PMC8918953/ /pubmed/35321260 http://dx.doi.org/10.34133/2022/9802969 Text en Copyright © 2022 Yasen Maimaitiyiming et al. https://creativecommons.org/licenses/by/4.0/Exclusive Licensee Science and Technology Review Publishing House. Distributed under a Creative Commons Attribution License (CC BY 4.0).
spellingShingle Perspective
Maimaitiyiming, Yasen
Yang, Tao
Wang, Qian Qian
Feng, Yan
Chen, Zhi
Björklund, Mikael
Wang, Fudi
Hu, Chonggao
Hsu, Chih-Hung
Naranmandura, Hua
Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreases Viral Load
title Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreases Viral Load
title_full Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreases Viral Load
title_fullStr Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreases Viral Load
title_full_unstemmed Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreases Viral Load
title_short Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreases Viral Load
title_sort heat treatment promotes ubiquitin-mediated proteolysis of sars-cov-2 rna polymerase and decreases viral load
topic Perspective
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8918953/
https://www.ncbi.nlm.nih.gov/pubmed/35321260
http://dx.doi.org/10.34133/2022/9802969
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