eIF2B-capturing viral protein NSs suppresses the integrated stress response

• DOI: 10.1038/s41467-021-27337-x
• Publication Date: 2021-12-07T11:02:38Z
• Authors: Kazuhiro Kashiwagi; Yuichi Shichino; Tatsuya Osaki; Ayako Sakamoto; Madoka Nishimoto; Mari Takahashi; Mari Mito; Friedemann Weber; Yoshiho Ikeuchi; Shintaro Iwasaki; Takuhiro Ito
• Keywords: Integrated stress response; eIF2; Thapsigargin

Abstract Various stressors such as viral infection lead to the suppression of cap-dependent translation and activation integrated stress response (ISR), since stress-induced phosphorylated eukaryotic initiation factor 2 [eIF2(αP)] tightly binds eIF2B prevent it from exchanging guanine nucleotide molecules on its substrate, unphosphorylated eIF2. Sandfly fever Sicilian virus (SFSV) evades this through interaction between nonstructural protein NSs host eIF2B. However, precise mechanism has remained unclear. Here, our cryo-electron microscopy (cryo-EM) analysis reveals that SFSV α-subunit in a competitive manner with eIF2(αP). Together NSs, retains exchange activity even presence eIF2(αP), line cryo-EM structures eIF2B•SFSV NSs•unphosphorylated eIF2 complex. A genome-wide ribosome profiling clarified expressed cultured human cells attenuates ISR triggered by thapsigargin, an endoplasmic reticulum inducer. Furthermore, introduced rat hippocampal neurons induced-pluripotent stem (iPS) cell-derived motor exhibits neuroprotective effects against ISR-inducing stress. Since inhibition is beneficial various neurological disease models, may be promising therapeutic inhibitor.