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eIF2B-capturing viral protein NSs suppresses the integrated stress response

View ORCID ProfileKazuhiro Kashiwagi, View ORCID ProfileYuichi Shichino, View ORCID ProfileTatsuya Osaki, View ORCID ProfileAyako Sakamoto, View ORCID ProfileMadoka Nishimoto, View ORCID ProfileMari Takahashi, View ORCID ProfileMari Mito, View ORCID ProfileFriedemann Weber, View ORCID ProfileYoshiho Ikeuchi, View ORCID ProfileShintaro Iwasaki, View ORCID ProfileTakuhiro Ito
doi: https://doi.org/10.1101/2021.06.07.447466
Kazuhiro Kashiwagi
1Laboratory for Translation Structural Biology, RIKEN Center for Biosystems Dynamics Research, Tsurumi-ku, Yokohama 230-0045, Japan
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Yuichi Shichino
2RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan
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Tatsuya Osaki
3Institute of Industrial Science, The University of Tokyo, Meguro-ku, Tokyo 153-8505, Japan
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Ayako Sakamoto
1Laboratory for Translation Structural Biology, RIKEN Center for Biosystems Dynamics Research, Tsurumi-ku, Yokohama 230-0045, Japan
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Madoka Nishimoto
1Laboratory for Translation Structural Biology, RIKEN Center for Biosystems Dynamics Research, Tsurumi-ku, Yokohama 230-0045, Japan
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Mari Takahashi
1Laboratory for Translation Structural Biology, RIKEN Center for Biosystems Dynamics Research, Tsurumi-ku, Yokohama 230-0045, Japan
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Mari Mito
2RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan
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Friedemann Weber
4Institute for Virology, FB10-Veterinary Medicine, Justus-Liebig University, Giessen D-35392, Germany
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Yoshiho Ikeuchi
3Institute of Industrial Science, The University of Tokyo, Meguro-ku, Tokyo 153-8505, Japan
5Institute for AI and Beyond, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
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  • For correspondence: yikeuchi@iis.u-tokyo.ac.jp shintaro.iwasaki@riken.jp takuhiro.ito@riken.jp
Shintaro Iwasaki
2RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan
6Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8561, Japan
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  • For correspondence: yikeuchi@iis.u-tokyo.ac.jp shintaro.iwasaki@riken.jp takuhiro.ito@riken.jp
Takuhiro Ito
1Laboratory for Translation Structural Biology, RIKEN Center for Biosystems Dynamics Research, Tsurumi-ku, Yokohama 230-0045, Japan
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  • For correspondence: yikeuchi@iis.u-tokyo.ac.jp shintaro.iwasaki@riken.jp takuhiro.ito@riken.jp
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SUMMARY

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 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 α-subunit of eIF2B in a competitive manner with eIF2(αP). Together with SFSV NSs, eIF2B exhibits normal nucleotide exchange activity even in the presence of eIF2(αP). 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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵8 Senior authors

  • ↵9 Lead Contact

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 08, 2021.
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eIF2B-capturing viral protein NSs suppresses the integrated stress response
Kazuhiro Kashiwagi, Yuichi Shichino, Tatsuya Osaki, Ayako Sakamoto, Madoka Nishimoto, Mari Takahashi, Mari Mito, Friedemann Weber, Yoshiho Ikeuchi, Shintaro Iwasaki, Takuhiro Ito
bioRxiv 2021.06.07.447466; doi: https://doi.org/10.1101/2021.06.07.447466
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eIF2B-capturing viral protein NSs suppresses the integrated stress response
Kazuhiro Kashiwagi, Yuichi Shichino, Tatsuya Osaki, Ayako Sakamoto, Madoka Nishimoto, Mari Takahashi, Mari Mito, Friedemann Weber, Yoshiho Ikeuchi, Shintaro Iwasaki, Takuhiro Ito
bioRxiv 2021.06.07.447466; doi: https://doi.org/10.1101/2021.06.07.447466

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