1. eIF2B-capturing viral protein NSs suppresses the integrated stress response
- Author
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Yuichi Shichino, Takuhiro Ito, Friedemann Weber, Kazuhiro Kashiwagi, Mari Takahashi, Madoka Nishimoto, Tatsuya Osaki, Shintaro Iwasaki, Mari Mito, Yoshiho Ikeuchi, and Ayako Sakamoto
- Subjects
Models, Molecular ,Phlebovirus ,Translation ,Viral protein ,Science ,Eukaryotic Initiation Factor-2 ,General Physics and Astronomy ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,Animal Diseases ,Cell Line ,Viral Proteins ,Eukaryotic translation ,medicine ,Animals ,Humans ,Integrated stress response ,Phosphorylation ,Rats, Wistar ,Neurons ,eIF2 ,Multidisciplinary ,biology ,Prokaryotic initiation factor-2 ,Chemistry ,Cryoelectron Microscopy ,Translation (biology) ,General Chemistry ,Rats ,Cell biology ,Eukaryotic Initiation Factor-2B ,eIF2B ,biology.protein ,Female ,Ribosomes ,Protein Binding - Abstract
Various stressors such as viral infection lead to the suppression of cap-dependent translation and the activation of the integrated stress response (ISR), since the stress-induced phosphorylated eukaryotic translation initiation factor 2 [eIF2(αP)] tightly binds to eIF2B to prevent it from exchanging guanine nucleotide molecules on its substrate, unphosphorylated eIF2. Sandfly fever Sicilian virus (SFSV) evades this cap-dependent translation suppression through the interaction between its nonstructural protein NSs and host eIF2B. However, its precise mechanism has remained unclear. Here, our cryo-electron microscopy (cryo-EM) analysis reveals that SFSV NSs binds to the α-subunit of eIF2B in a competitive manner with eIF2(αP). Together with SFSV NSs, eIF2B retains nucleotide exchange activity even in the presence of eIF2(αP), in line with the cryo-EM structures of the eIF2B•SFSV NSs•unphosphorylated eIF2 complex. A genome-wide ribosome profiling analysis clarified that SFSV NSs expressed in cultured human cells attenuates the ISR triggered by thapsigargin, an endoplasmic reticulum stress inducer. Furthermore, SFSV NSs introduced in rat hippocampal neurons and human induced-pluripotent stem (iPS) cell-derived motor neurons exhibits neuroprotective effects against the ISR-inducing stress. Since ISR inhibition is beneficial in various neurological disease models, SFSV NSs may be a promising therapeutic ISR inhibitor., Here the authors show that a viral protein interferes with the binding of phosphorylated eIF2 to eIF2B, thereby suppressing the host integrated stress response (ISR). This suppression of the ISR abrogates translational changes of the host and ameliorates neurite degradation under stress.
- Published
- 2021