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PKR Binds Enterovirus IRESs, Displaces Host Translation Factors, and Impairs Viral Translation to Enable Innate Antiviral Signaling
10.1128/mbio.00854-22
Mikhail I. Dobrikov
Elena Y. Dobrikova
Zachary P. McKay
Jonathan P. Kastan
Michael C. Brown
Matthias Gromeier
Research Article
Research Article
dendritic cell
IRES
MDA5
PKR
TBK1
eIF4G
interferon
poliovirus
translation
American Society for Microbiology
Dobrikov et al.
Copyright © 2022 Dobrikov et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
20220602
2022
ABSTRACT
For RNA virus families except Picornaviridae, viral RNA sensing includes Toll-like receptors and/or RIG-I. Picornavirus RNAs, whose 5′ termini are shielded by a genome-linked protein, are predominately recognized by MDA5. This has important ramifications for adaptive immunity, as MDA5-specific patterns of type-I interferon (IFN) release are optimal for CD4+T cell TH1 polarization and CD8+T cell priming. We are exploiting this principle for cancer immunotherapy with recombinant poliovirus (PV), PVSRIPO, the type 1 (Sabin) PV vaccine containing a rhinovirus type 2 internal ribosomal entry site (IRES). Here we show that PVSRIPO-elicited MDA5 signaling is preceded by early sensing of the IRES by the double-stranded (ds)RNA-activated protein kinase (PKR). PKR binding to IRES stem-loop domains 5–6 led to dimerization and autoactivation, displaced host translation initiation factors, and suppressed viral protein synthesis. Early PKR-mediated antiviral responses tempered incipient viral translation and the activity of cytopathogenic viral proteinases, setting up accentuated MDA5 innate inflammation in response to PVSRIPO infection.
IMPORTANCE Among the RIG-I-like pattern recognition receptors, MDA5 stands out because it senses long dsRNA duplexes independent of their 5′ features (RIG-I recognizes viral [v]RNA 5′-ppp blunt ends). Uniquely among RNA viruses, the innate defense against picornaviruses is controlled by MDA5. We show that prior to engaging MDA5, recombinant PV RNA is sensed upon PKR binding to the viral IRES at a site that overlaps with the footprint for host translation factors mediating 40S subunit recruitment. Our study demonstrates that innate antiviral type-I IFN responses orchestrated by MDA5 involve separate innate modules that recognize distinct vRNA features and interfere with viral functions at multiple levels.
20220324
20220516
2150-7511
Adobe LiveCycle PDF Generator; modified using iText® 5.5.13.2 ©2000-2020 iText Group NV (AGPL-version)2022-06-23T14:57:01-07:00
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