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Published Research in Science Advances: CReP mediates selective translation initiation at the endoplasmic reticulum

Journal authors for the below study:
Jonathan P. Kastan, Elena Y. Dobrikova, Jeffrey D. Bryant, Matthias Gromeier

Cells respond to environmental stress with coordinated transcriptional, translational, and posttranslational gene expression changes. The pivotal event in the integrated stress response (ISR) is phosphorylation of serine-51 of the α subunit of eukaryotic initiation factor 2 (eIF2). The ISR globally curtails translation initiation via the eIF2–guanosine triphosphate (GTP)–initiator methionyl transfer RNA (tRNA) in the ternary complex by inhibiting eIF2B-mediated exchange of guanosine diphosphate for GTP on eIF2. Coincident with this suppression of global protein synthesis is the induction of transcription factor ATF4 and eIF2α–protein phosphatase 1 (PP1) scaffold GADD34, which coordinate downstream ISR programs to restore homeostasis or, with unrelenting stress, activate programmed cell death.

Double-stranded RNA (dsRNA) intermediates generated during viral infection induce p-eIF2α(S51) via the dsRNA-activated protein kinase R (PKR), one of four eIF2α(S51)-directed kinases. eIF2α(S51) phosphorylation is detrimental to most human viral pathogens, triggering the evolution of elaborate viral countermeasures. Enteroviruses require eIF2 for translation initiation at their positive strand RNA genomes; yet, they maintain viral translation in the face of robust eIF2α(S51) phosphorylation. They achieve this without specific mechanisms to counter PKR activation or eIF2α(S51) phosphorylation.

Enteroviruses reorganize the secretory pathway into replication complexes consisting of components derived from endoplasmic reticulum (ER), Golgi, and lysosomes, where they concentrate cofactors required by their RNA-dependent RNA polymerases. How this locale may be exploited to provide protection from cellular antiviral responses remains largely unexplored.

This study of p-eIF2α(S51)’s role in shaping poliovirus:host relations uncovered that CReP, an ER-localized PP1-eIF2α scaffold, determines partitioning of translation initiation factors at the ER and defines a spatially and functionally distinct translation initiation compartment at this site. CReP promotes the expression of BiP, an HSP70-type chaperone in the ER and major regulator of the cellular unfolded protein response. BiP translation, like poliovirus (PV), is maintained during the ISR, and we posit that PV and BiP translation evades inhibitory effects of p-eIF2α(S51) via CReP:eIF2α at the ER. This phenomenon explains earlier seminal findings that BiP translation is maintained during the host protein synthesis shutoff elicited by PV. Overall, this investigation demonstrates that CReP engages canonical translation initiation machinery at the ER, allowing for ongoing local protein synthesis in the presence of global translation repression mediated by the ISR.

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