Inhibition of HeLa cell protein synthesis following poliovirus infection correlates with the proteolysis of a 220,000-dalton polypeptide associated with eucaryotic initiation factor 3 and a cap binding protein complex.

Etchison, Diane; Milburn, Susan C.; Edery, Isaac; Sonenberg, Nahum; Hershey, John W.B.

doi:10.1016/s0021-9258(18)33352-0

Cited by 539 publications

(52 citation statements)

References 23 publications

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“…Among them were YTHDF1 and YTHDF3. Here, we show that YTHDF1, 2, and 3 are cleaved in EV-infected HeLa cells at a rate similar to that of eIF4G1, the emblematic host cell target for 2A pro (18). YTHDF3 depletion enhanced viral translation and replication exclusively in cell lines that mount robust, protective innate antiviral responses to infection.…”

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confidence: 72%

“…Deciphering the effects of YTHDF3 depletion on the innate host response to PVSRIPO infection indicated that the YTHDF proteins act at a step after IFN-b/IFN-l1 release, implicating YTHDF3 as a mediator of JAK/STAT1 signaling. The classic EV-host cell interference event, 2A pro activities associated with cleavage of eIF4G1/2, contributes to blocking host m 7 G-cap-dependent translation (18). A 2A pro -driven viral program to subvert host defenses in infected host cells may encompass concerted cleavages of YTHDF proteins and of eIF4G1/2, preventing ISG induction.…”

Section: Discussionmentioning

confidence: 99%

“…Enteroviruses (EV) encode two cysteine proteases; 3C pro processes most polyprotein cleavages. Meanwhile, 2A pro mainly cleaves the polyprotein at the P1-P2 junction (17) but degrades host proteins with vital functions in translation (eukaryotic initiation factor [eIF] 4G1/2) and nucleocytoplasmic transport (nuclear pore complex components Nup153 and p62) (18,19).…”

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confidence: 99%

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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

Kastan

Tremblay

Brown

et al. 2021

mBio

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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. IMPORTANCE It is believed that ∼7,000 messenger RNAs (mRNAs) are subject to N6-methyladenosine modification. The biological significance of this remains mysterious. The YTHDF m6A readers are three related proteins with high affinity for m6A-modified mRNA, yet their biological functions remain obscure. We discovered that polio/enteroviruses elicit very early proteolysis of YTHDF1 to 3 in infected cells. Our research demonstrates that YTHDF3 acts as a positive regulator of antiviral JAK/STAT signaling in response to positive single-strand RNA virus infection, enabling type I interferon (IFN)-mediated gene regulatory programs to unfurl in infected cells. Our observation of viral degradation of the YTHDF proteins demonstrates that they are key response modifiers in the innate antiviral immune response.

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confidence: 72%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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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

Kastan

Tremblay

Brown

et al. 2021

mBio

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“…Pioneering studies of picornavirus-infected cells showed the cleavage of eIF4G (Etchison et al, 1982), but proteolysis of other host factors also contribute to virus pathogenesis (reviewed by Lloyd, 2006). Transcription factors and other proteins involved in gene expression and cell signalling are cleaved during picornavirus infection (Clark & Dasgupta, 1990;Falk et al, 1990;Yalamanchili et al, 1996).…”

Section: Ires Activity Is Resistant To Specific Host Protein Cleavage and Phosphorylation Changes Occurring In Infected Cellsmentioning

confidence: 99%

New insights into internal ribosome entry site elements relevant for viral gene expression

Martínez‐Salas

Pacheco

Serrano

et al. 2008

Journal of General Virology

119

106

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A distinctive feature of positive-strand RNA viruses is the presence of high-order structural elements at the untranslated regions (UTR) of the genome that are essential for viral RNA replication. The RNA of all members of the family Picornaviridae initiate translation internally, via an internal ribosome entry site (IRES) element present in the 59 UTR. IRES elements consist of cis-acting RNA structures that usually require specific RNA-binding proteins for translational machinery recruitment. This specialized mechanism of translation initiation is shared with other viral RNAs, e.g. from hepatitis C virus and pestivirus, and represents an alternative to the cap-dependent mechanism. In cells infected with many picornaviruses, proteolysis or changes in phosphorylation of key host factors induces shut off of cellular protein synthesis. This event occurs simultaneously with the synthesis of viral gene products since IRES activity is resistant to the modifications of the host factors. Viral gene expression and RNA replication in positive-strand viruses is further stimulated by viral RNA circularization, involving direct RNA-RNA contacts between the 59 and 39 ends as well as RNA-binding protein bridges. In this review, we discuss novel insights into the mechanisms that control picornavirus gene expression and compare them to those operating in other positive-strand RNA viruses.

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“…Infected cell extracts do not support the translation of capped RNAs (7,34) or their attachment to the CBP complex (16), but both activities can be restored by the addition of CBP complex from uninfected cells (17,41). In vivo, the decline in host protein synthesis is preceded by specific cleavage of a 220,000-dalton protein (P220) which is part of the CBP complex (6). It has been proposed that the complex is inactivated by this cleavage (6).…”

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confidence: 99%

Poliovirus Mutant That Does Not Selectively Inhibit Host Cell Protein Synthesis

Sonenberg¹,

Baltimore²

1985

Molecular and Cellular Biology

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A poliovirus type I (Mahoney strain) mutant was obtained by inserting three base pairs into an infectious cDNA clone. The extra amino acid encoded by the insertion was in the amino-terminal (protein 8) portion of the P2 segment of the polyprotein. The mutant virus makes small plaques on HeLa and monkey kidney (CV-1) cells at all temperatures. It lost the ability to mediate the selective inhibition of host cell translation which ordinarily occurs in the first few hours after infection. As an apparent consequence, the mutant synthesizes far less protein than does wild-type virus. In mutant-infected CV-1 cells enough protein was produced to permit a normal course of RNA replication, but the yield of progeny virus was very low. In mutant-infected HeLa cells there was a premature cessation of both cellular and viral protein synthesis followed by a premature halt of viral RNA synthesis. This nonspecific translational inhibition was distinguishable from wild-type-mediated inhibition and did not appear to be part of an interferon or heat shock response. Because the mutant is recessive, our results imply that (at least in HeLa cells) wild-type poliovirus not only actively inhibits translation of cellular mRNAs, but also avoids early inhibition of its own protein synthesis. Cleavage of the cap-binding complex protein P220, which has been associated with the selective inhibition of capped mRNA translation, did not occur in mutant-infected cells. This result supports the hypothesis that cleavage of P220 plays an important role in normal poliovirus-mediated translational inhibition.

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Inhibition of HeLa cell protein synthesis following poliovirus infection correlates with the proteolysis of a 220,000-dalton polypeptide associated with eucaryotic initiation factor 3 and a cap binding protein complex.

Cited by 539 publications

References 23 publications

Enterovirus 2A ^pro Cleavage of the YTHDF m ⁶ A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling

Enterovirus 2A ^pro Cleavage of the YTHDF m ⁶ A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling

New insights into internal ribosome entry site elements relevant for viral gene expression

Poliovirus Mutant That Does Not Selectively Inhibit Host Cell Protein Synthesis

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Inhibition of HeLa cell protein synthesis following poliovirus infection correlates with the proteolysis of a 220,000-dalton polypeptide associated with eucaryotic initiation factor 3 and a cap binding protein complex.

Cited by 539 publications

References 23 publications

Enterovirus 2A pro Cleavage of the YTHDF m 6 A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling

Enterovirus 2A pro Cleavage of the YTHDF m 6 A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling

New insights into internal ribosome entry site elements relevant for viral gene expression

Poliovirus Mutant That Does Not Selectively Inhibit Host Cell Protein Synthesis

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Product

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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

Enterovirus 2A ^pro Cleavage of the YTHDF m ⁶ A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling