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Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1
COVID-19, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), has presented a serious risk to global public health. The viral main protease M(pro) (also called 3Cl(pro)) encoded by NSP5 is an enzyme essential for viral replication. However, very few host proteins have been experimentally...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449311/ https://www.ncbi.nlm.nih.gov/pubmed/34452991 http://dx.doi.org/10.1073/pnas.2107108118 |
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author | Zhang, Shilei Wang, Jingfeng Cheng, Genhong |
author_facet | Zhang, Shilei Wang, Jingfeng Cheng, Genhong |
author_sort | Zhang, Shilei |
collection | PubMed |
description | COVID-19, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), has presented a serious risk to global public health. The viral main protease M(pro) (also called 3Cl(pro)) encoded by NSP5 is an enzyme essential for viral replication. However, very few host proteins have been experimentally validated as targets of 3Clpro. Here, through bioinformatics analysis of 300 interferon stimulatory genes (ISGs) based on the prediction method NetCorona, we identify RNF20 (Ring Finger Protein 20) as a novel target of 3Clpro. We have also provided evidence that 3Clpro, but not the mutant 3Clpro(C145A) without catalytic activity, cleaves RNF20 at a conserved Gln521 across species, which subsequently prevents SREBP1 from RNF20-mediated degradation and promotes SARS-CoV-2 replication. We show that RNA interference (RNAi)-mediated depletion of either RNF20 or RNF40 significantly enhances viral replication, indicating the antiviral role of RNF20/RNF40 complex against SARS-CoV-2. The involvement of SREBP1 in SARS-CoV-2 infection is evidenced by a decrease of viral replication in the cells with SREBP1 knockdown and inhibitor AM580. Taken together, our findings reveal RNF20 as a novel host target for SARS-CoV-2 main protease and indicate that 3Clpro inhibitors may treat COVID-19 through not only blocking viral polyprotein cleavage but also enhancing host antiviral response. |
format | Online Article Text |
id | pubmed-8449311 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-84493112021-10-04 Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1 Zhang, Shilei Wang, Jingfeng Cheng, Genhong Proc Natl Acad Sci U S A Biological Sciences COVID-19, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), has presented a serious risk to global public health. The viral main protease M(pro) (also called 3Cl(pro)) encoded by NSP5 is an enzyme essential for viral replication. However, very few host proteins have been experimentally validated as targets of 3Clpro. Here, through bioinformatics analysis of 300 interferon stimulatory genes (ISGs) based on the prediction method NetCorona, we identify RNF20 (Ring Finger Protein 20) as a novel target of 3Clpro. We have also provided evidence that 3Clpro, but not the mutant 3Clpro(C145A) without catalytic activity, cleaves RNF20 at a conserved Gln521 across species, which subsequently prevents SREBP1 from RNF20-mediated degradation and promotes SARS-CoV-2 replication. We show that RNA interference (RNAi)-mediated depletion of either RNF20 or RNF40 significantly enhances viral replication, indicating the antiviral role of RNF20/RNF40 complex against SARS-CoV-2. The involvement of SREBP1 in SARS-CoV-2 infection is evidenced by a decrease of viral replication in the cells with SREBP1 knockdown and inhibitor AM580. Taken together, our findings reveal RNF20 as a novel host target for SARS-CoV-2 main protease and indicate that 3Clpro inhibitors may treat COVID-19 through not only blocking viral polyprotein cleavage but also enhancing host antiviral response. National Academy of Sciences 2021-09-14 2021-08-27 /pmc/articles/PMC8449311/ /pubmed/34452991 http://dx.doi.org/10.1073/pnas.2107108118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Zhang, Shilei Wang, Jingfeng Cheng, Genhong Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1 |
title | Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1 |
title_full | Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1 |
title_fullStr | Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1 |
title_full_unstemmed | Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1 |
title_short | Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1 |
title_sort | protease cleavage of rnf20 facilitates coronavirus replication via stabilization of srebp1 |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449311/ https://www.ncbi.nlm.nih.gov/pubmed/34452991 http://dx.doi.org/10.1073/pnas.2107108118 |
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