Inhibition of the integrated stress response by viral proteins that block p-eIF2-eIF2B association.

Nature Microbiology
Huib H RabouwFrank J M van Kuppeveld

Abstract

Eukaryotic cells, when exposed to environmental or internal stress, activate the integrated stress response (ISR) to restore homeostasis and promote cell survival. Specific stress stimuli prompt dedicated stress kinases to phosphorylate eukaryotic initiation factor 2 (eIF2). Phosphorylated eIF2 (p-eIF2) in turn sequesters the eIF2-specific guanine exchange factor eIF2B to block eIF2 recycling, thereby halting translation initiation and reducing global protein synthesis. To circumvent stress-induced translational shutdown, viruses encode ISR antagonists. Those identified so far prevent or reverse eIF2 phosphorylation. We now describe two viral proteins-one from a coronavirus and the other from a picornavirus-that have independently acquired the ability to counteract the ISR at its very core by acting as a competitive inhibitor of p-eIF2-eIF2B interaction. This allows continued formation of the eIF2-GTP-Met-tRNAi ternary complex and unabated global translation at high p-eIF2 levels that would otherwise cause translational arrest. We conclude that eIF2 and p-eIF2 differ in their interaction with eIF2B to such effect that p-eIF2-eIF2B association can be selectively inhibited.

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Citations

Jan 22, 2021·Current Eye Research·Hsiao-Sang ChuJames Foster
Mar 5, 2021·Frontiers in Immunology·Kristin L RoscheDana K Shaw
Aug 26, 2021·Molecular Biology of the Cell·Triana AmenDaniel Kaganovich

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Datasets Mentioned

BETA
PXD011879

Methods Mentioned

BETA
transfection
flow cytometry
fluorescence microscopy
tandem affinity purification
pull-down
transfections
affinity purification
electron microscopy
PCR
co-immunoprecipitation

Software Mentioned

BLAST
MEGA X
XlinkX
Mascot
ImageJ
Proteome Discoverer
CRAPome
Percolator
NEEDLE
STRING ( Search Tool for the Retrieval of Interacting Genes / ...

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