Journal article

Publication year: 2021

Journal: Nature Communications

Volume number: 12

Issue number: 1

eISSN: 2041-1723

Open access status: Gold

DOI Link: https://doi.org/10.1038/s41467-021-27337-x

Publisher: Nature Research

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(alpha P)] 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 alpha-subunit of eIF2B in a competitive manner with eIF2(alpha P). Together with SFSV NSs, eIF2B retains nucleotide exchange activity even in the presence of eIF2(alpha P), in line with the cryo-EM structures of the eIF2B center dot SFSV NSs center dot 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.

Harvard Citation style: Kashiwagi, K., Shichino, Y., Osaki, T., Sakamoto, A., Nishimoto, M., Takahashi, M., et al. (2021) eIF2B-capturing viral protein NSs suppresses the integrated stress response, Nature Communications, 12(1), Article 7102. https://doi.org/10.1038/s41467-021-27337-x

APA Citation style: Kashiwagi, K., Shichino, Y., Osaki, T., Sakamoto, A., Nishimoto, M., Takahashi, M., Mito, M., Weber, F., Ikeuchi, Y., Iwasaki, S., & Ito, T. (2021). eIF2B-capturing viral protein NSs suppresses the integrated stress response. Nature Communications. 12(1), Article 7102. https://doi.org/10.1038/s41467-021-27337-x