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Enterovirus 2A(pro) Cleavage of the YTHDF m(6)A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling
Enteroviruses (EV) deploy two proteases that mediate viral polyprotein cleavage and host cell manipulation. Here, we report that EV 2A proteases cleave all three members of the YTHDF protein family, cytosolic N(6)-methyladenosine (m(6)A) “readers” that regulate target mRNA fate. YTHDF protein cleava...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092205/ https://www.ncbi.nlm.nih.gov/pubmed/33849973 http://dx.doi.org/10.1128/mBio.00116-21 |
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author | Kastan, Jonathan P. Tremblay, Martine W. Brown, Michael C. Trimarco, Joseph D. Dobrikova, Elena Y. Dobrikov, Mikhail I. Gromeier, Matthias |
author_facet | Kastan, Jonathan P. Tremblay, Martine W. Brown, Michael C. Trimarco, Joseph D. Dobrikova, Elena Y. Dobrikov, Mikhail I. Gromeier, Matthias |
author_sort | Kastan, Jonathan P. |
collection | PubMed |
description | Enteroviruses (EV) deploy two proteases that mediate viral polyprotein cleavage and host cell manipulation. Here, we report that EV 2A proteases cleave all three members of the YTHDF protein family, cytosolic N(6)-methyladenosine (m(6)A) “readers” that regulate target mRNA fate. YTHDF protein cleavage occurs very early during infection, before viral translation is detected or cytopathogenic effects are observed. Preemptive YTHDF protein depletion enhanced viral translation and replication but only in cells with restrained viral translation, signs of inefficient 2A protease activity, and protective innate host immune responses. This effect corresponded with repression of interferon (IFN)-stimulated gene (ISG) induction, while type I/III IFN production was not significantly altered. Moreover, YTHDF3 depletion impaired JAK/STAT signaling in cells treated with type I, but not type II, IFN. YTHDF3 depletion’s stimulatory effect on viral dynamics was dampened by JAK/STAT blockade and enhanced by type I IFN pretreatment of cells. We propose that EV 2A proteases cleave YTHDF proteins to antagonize ISG induction in infected cells. |
format | Online Article Text |
id | pubmed-8092205 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-80922052021-05-04 Enterovirus 2A(pro) Cleavage of the YTHDF m(6)A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling Kastan, Jonathan P. Tremblay, Martine W. Brown, Michael C. Trimarco, Joseph D. Dobrikova, Elena Y. Dobrikov, Mikhail I. Gromeier, Matthias mBio Research Article Enteroviruses (EV) deploy two proteases that mediate viral polyprotein cleavage and host cell manipulation. Here, we report that EV 2A proteases cleave all three members of the YTHDF protein family, cytosolic N(6)-methyladenosine (m(6)A) “readers” that regulate target mRNA fate. YTHDF protein cleavage occurs very early during infection, before viral translation is detected or cytopathogenic effects are observed. Preemptive YTHDF protein depletion enhanced viral translation and replication but only in cells with restrained viral translation, signs of inefficient 2A protease activity, and protective innate host immune responses. This effect corresponded with repression of interferon (IFN)-stimulated gene (ISG) induction, while type I/III IFN production was not significantly altered. Moreover, YTHDF3 depletion impaired JAK/STAT signaling in cells treated with type I, but not type II, IFN. YTHDF3 depletion’s stimulatory effect on viral dynamics was dampened by JAK/STAT blockade and enhanced by type I IFN pretreatment of cells. We propose that EV 2A proteases cleave YTHDF proteins to antagonize ISG induction in infected cells. American Society for Microbiology 2021-04-13 /pmc/articles/PMC8092205/ /pubmed/33849973 http://dx.doi.org/10.1128/mBio.00116-21 Text en Copyright © 2021 Kastan et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Kastan, Jonathan P. Tremblay, Martine W. Brown, Michael C. Trimarco, Joseph D. Dobrikova, Elena Y. Dobrikov, Mikhail I. Gromeier, Matthias Enterovirus 2A(pro) Cleavage of the YTHDF m(6)A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling |
title | Enterovirus 2A(pro) Cleavage of the YTHDF m(6)A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling |
title_full | Enterovirus 2A(pro) Cleavage of the YTHDF m(6)A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling |
title_fullStr | Enterovirus 2A(pro) Cleavage of the YTHDF m(6)A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling |
title_full_unstemmed | Enterovirus 2A(pro) Cleavage of the YTHDF m(6)A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling |
title_short | Enterovirus 2A(pro) Cleavage of the YTHDF m(6)A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling |
title_sort | enterovirus 2a(pro) cleavage of the ythdf m(6)a readers implicates ythdf3 as a mediator of type i interferon-driven jak/stat signaling |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092205/ https://www.ncbi.nlm.nih.gov/pubmed/33849973 http://dx.doi.org/10.1128/mBio.00116-21 |
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