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TitleeIF2B-capturing viral protein NSs suppresses the integrated stress response.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 7102, Year 2021
Publish dateDec 7, 2021
AuthorsKazuhiro Kashiwagi / Yuichi Shichino / Tatsuya Osaki / Ayako Sakamoto / Madoka Nishimoto / Mari Takahashi / Mari Mito / Friedemann Weber / Yoshiho Ikeuchi / Shintaro Iwasaki / Takuhiro Ito /
PubMed AbstractVarious 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 ...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.
External linksNat Commun / PubMed:34876589 / PubMed Central
MethodsEM (single particle)
Resolution2.27 - 3.59 Å
Structure data

31472

7f64

EMDB-31472, PDB-7f64:
eIF2B-SFSV NSs
Method: EM (single particle) / Resolution: 2.42 Å

31474

7f66

EMDB-31474, PDB-7f66:
eIF2B-SFSV NSs-1-eIF2
Method: EM (single particle) / Resolution: 2.76 Å

31475

7f67

EMDB-31475, PDB-7f67:
eIF2B-SFSV NSs-2-eIF2
Method: EM (single particle) / Resolution: 3.59 Å

32023

7vlk

EMDB-32023, PDB-7vlk:
eIF2B-SFSV NSs C2-imposed
Method: EM (single particle) / Resolution: 2.27 Å

Source
  • homo sapiens (human)
  • sandfly fever sicilian virus
KeywordsTRANSLATION / translation initiation factor / viral protein / Complex

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