Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Shilei, Wang, Jingfeng, Cheng, Genhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2021
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
_version_ 1784569405787602944
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
work_keys_str_mv AT zhangshilei proteasecleavageofrnf20facilitatescoronavirusreplicationviastabilizationofsrebp1
AT wangjingfeng proteasecleavageofrnf20facilitatescoronavirusreplicationviastabilizationofsrebp1
AT chenggenhong proteasecleavageofrnf20facilitatescoronavirusreplicationviastabilizationofsrebp1