Understanding Selenium and Glutathione as Antiviral Factors in COVID-19: Does the Viral Mpro Protease Target Host Selenoproteins and Glutathione Synthesis?
Identifieur interne : 000004 ( Main/Exploration ); précédent : 000003; suivant : 000005Understanding Selenium and Glutathione as Antiviral Factors in COVID-19: Does the Viral Mpro Protease Target Host Selenoproteins and Glutathione Synthesis?
Auteurs : Ethan Will Taylor [États-Unis] ; Wilson Radding [États-Unis]Source :
- Frontiers in nutrition [ 2296-861X ] ; 2020.
Abstract
Glutathione peroxidases (GPX), a family of antioxidant selenoenzymes, functionally link selenium and glutathione, which both show correlations with clinical outcomes in COVID-19. Thus, it is highly significant that cytosolic GPX1 has been shown to interact with an inactive C145A mutant of Mpro, the main cysteine protease of SARS-CoV-2, but not with catalytically active wild-type Mpro. This seemingly anomalous result is what might be expected if GPX1 is a substrate for the active protease, leading to its fragmentation. We show that the GPX1 active site sequence is substantially similar to a known Mpro cleavage site, and is identified as a potential cysteine protease site by the Procleave algorithm. Proteolytic knockdown of GPX1 is highly consistent with previously documented effects of recombinant SARS-CoV Mpro in transfected cells, including increased reactive oxygen species and NF-κB activation. Because NF-κB in turn activates many pro-inflammatory cytokines, this mechanism could contribute to increased inflammation and cytokine storms observed in COVID-19. Using web-based protease cleavage site prediction tools, we show that Mpro may be targeting not only GPX1, but several other selenoproteins including SELENOF and thioredoxin reductase 1, as well as glutamate-cysteine ligase, the rate-limiting enzyme for glutathione synthesis. This hypothesized proteolytic knockdown of components of both the thioredoxin and glutaredoxin systems is consistent with a viral strategy to inhibit DNA synthesis, to increase the pool of ribonucleotides for RNA synthesis, thereby enhancing virion production. The resulting "collateral damage" of increased oxidative stress and inflammation would be exacerbated by dietary deficiencies of selenium and glutathione precursors.
DOI: 10.3389/fnut.2020.00143
PubMed: 32984400
PubMed Central: PMC7492384
Affiliations:
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Thus, it is highly significant that cytosolic GPX1 has been shown to interact with an inactive C145A mutant of M<sup>pro</sup>, the main cysteine protease of SARS-CoV-2, but not with catalytically active wild-type M<sup>pro</sup>. This seemingly anomalous result is what might be expected if GPX1 is a substrate for the active protease, leading to its fragmentation. We show that the GPX1 active site sequence is substantially similar to a known M<sup>pro</sup> cleavage site, and is identified as a potential cysteine protease site by the Procleave algorithm. Proteolytic knockdown of GPX1 is highly consistent with previously documented effects of recombinant SARS-CoV M<sup>pro</sup> in transfected cells, including increased reactive oxygen species and NF-κB activation. Because NF-κB in turn activates many pro-inflammatory cytokines, this mechanism could contribute to increased inflammation and cytokine storms observed in COVID-19. Using web-based protease cleavage site prediction tools, we show that M<sup>pro</sup> may be targeting not only GPX1, but several other selenoproteins including SELENOF and thioredoxin reductase 1, as well as glutamate-cysteine ligase, the rate-limiting enzyme for glutathione synthesis. This hypothesized proteolytic knockdown of components of both the thioredoxin and glutaredoxin systems is consistent with a viral strategy to inhibit DNA synthesis, to increase the pool of ribonucleotides for RNA synthesis, thereby enhancing virion production. The resulting "collateral damage" of increased oxidative stress and inflammation would be exacerbated by dietary deficiencies of selenium and glutathione precursors.</div></front></TEI><pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">32984400</PMID><DateRevised><Year>2020</Year><Month>10</Month><Day>01</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Print">2296-861X</ISSN><JournalIssue CitedMedium="Print"><Volume>7</Volume><PubDate><Year>2020</Year></PubDate></JournalIssue><Title>Frontiers in nutrition</Title><ISOAbbreviation>Front Nutr</ISOAbbreviation></Journal><ArticleTitle>Understanding Selenium and Glutathione as Antiviral Factors in COVID-19: Does the Viral M<sup>pro</sup> Protease Target Host Selenoproteins and Glutathione Synthesis?</ArticleTitle><Pagination><MedlinePgn>143</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.3389/fnut.2020.00143</ELocationID><Abstract><AbstractText>Glutathione peroxidases (GPX), a family of antioxidant selenoenzymes, functionally link selenium and glutathione, which both show correlations with clinical outcomes in COVID-19. Thus, it is highly significant that cytosolic GPX1 has been shown to interact with an inactive C145A mutant of M<sup>pro</sup>, the main cysteine protease of SARS-CoV-2, but not with catalytically active wild-type M<sup>pro</sup>. This seemingly anomalous result is what might be expected if GPX1 is a substrate for the active protease, leading to its fragmentation. We show that the GPX1 active site sequence is substantially similar to a known M<sup>pro</sup> cleavage site, and is identified as a potential cysteine protease site by the Procleave algorithm. Proteolytic knockdown of GPX1 is highly consistent with previously documented effects of recombinant SARS-CoV M<sup>pro</sup> in transfected cells, including increased reactive oxygen species and NF-κB activation. Because NF-κB in turn activates many pro-inflammatory cytokines, this mechanism could contribute to increased inflammation and cytokine storms observed in COVID-19. Using web-based protease cleavage site prediction tools, we show that M<sup>pro</sup> may be targeting not only GPX1, but several other selenoproteins including SELENOF and thioredoxin reductase 1, as well as glutamate-cysteine ligase, the rate-limiting enzyme for glutathione synthesis. This hypothesized proteolytic knockdown of components of both the thioredoxin and glutaredoxin systems is consistent with a viral strategy to inhibit DNA synthesis, to increase the pool of ribonucleotides for RNA synthesis, thereby enhancing virion production. The resulting "collateral damage" of increased oxidative stress and inflammation would be exacerbated by dietary deficiencies of selenium and glutathione precursors.</AbstractText><CopyrightInformation>Copyright © 2020 Taylor and Radding.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Taylor</LastName><ForeName>Ethan Will</ForeName><Initials>EW</Initials><AffiliationInfo><Affiliation>Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, NC, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Radding</LastName><ForeName>Wilson</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, NC, United States.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal 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