Enterovirus 2A pro Cleavage of the YTHDF m 6 A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling
| Autor: | Mikhail I. Dobrikov, Joseph D. Trimarco, Michael C. Brown, Martine W. Tremblay, Elena Y. Dobrikova, Matthias Gromeier, Jonathan P. Kastan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
YTHDF proteins
Proteases 2A protease Biology type III interferon Microbiology stat Cell Line m6A modification Viral Proteins 03 medical and health sciences 0302 clinical medicine Immune system Interferon Virology medicine Humans innate immunity Janus Kinases 030304 developmental biology 0303 health sciences Messenger RNA Innate immune system poliovirus enterovirus Interferon-stimulated gene Viral translation RNA-Binding Proteins Immunity Innate QR1-502 Cell biology Jak/Stat signaling STAT Transcription Factors interferon stimulated gene 030220 oncology & carcinogenesis Interferon Type I Proteolysis type I interferon Research Article HeLa Cells Signal Transduction medicine.drug |
| Zdroj: | mBio, Vol 12, Iss 2 (2021) mBio |
| ISSN: | 2150-7511 |
| Popis: | It is believed that ∼7,000 messenger RNAs (mRNAs) are subject to N6-methyladenosine modification. The biological significance of this remains mysterious. 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 N6-methyladenosine (m6A) “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. |
| Databáze: | OpenAIRE |
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