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bioRxiv · 10.1101/2021.06.07.447466

eIF2B-capturing viral protein NSs suppresses the integrated stress response

Kashiwagi, K.·Shichino, Y.·Osaki, T.·Sakamoto, A.·Nishimoto, M.·Takahashi, M.·Mito, M.·Weber, F.·Ikeuchi, Y.·Iwasaki, S.·Ito, T.
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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(P)] tightly binds to eIF2B to prevent it from exchanging guanine nucleotides on unphosphorylated eIF2. Sandfly fever Sicilian virus (SFSV) evades this cap-dependent translation suppression through the interaction between its nonstructural protein NSs and host eIF2B. Our cryo-electron microscopy (cryo-EM) analysis revealed that SFSV NSs binds to the -subunit of eIF2B in a competitive manner with eIF2(P). Together with SFSV NSs, eIF2B exhibits normal nucleotide exchange activity even in the presence of eIF2(P). A genome-wide ribosome profiling analysis clarified that SFSV NSs in human cultured cells attenuates the ISR. Furthermore, SFSV NSs exhibited neuroprotective effects against the ISR-inducing stress. Since the ISR inhibition is beneficial in various neurological disease models, SFSV NSs is promising as a therapeutic ISR inhibitor.

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Kashiwagi, K., Shichino, Y., Osaki, T., Sakamoto, A., Nishimoto, M., Takahashi, M., Mito, M., Weber, F., Ikeuchi, Y., Iwasaki, S., Ito, T.. 2021-06-08. eIF2B-capturing viral protein NSs suppresses the integrated stress response. https://doi.org/10.1101/2021.06.07.447466

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