eIF2B-capturing viral protein NSs suppresses the integrated stress response

Area of Science:

• Molecular Virology
• Cellular Stress Response
• Neurobiology

Background:

• Viral infections often trigger the integrated stress response (ISR), suppressing host protein synthesis via phosphorylated eukaryotic translation initiation factor 2 [eIF2(αP)].
• Sandfly fever Sicilian virus (SFSV) utilizes its nonstructural protein NSs to counteract this cap-dependent translation suppression, but the mechanism is poorly understood.

Purpose of the Study:

• To elucidate the precise mechanism by which SFSV NSs interacts with host factor eIF2B to evade ISR-mediated translation inhibition.
• To investigate the potential therapeutic applications of SFSV NSs as an inhibitor of the ISR in neurological contexts.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine the structural basis of SFSV NSs interaction with eIF2B and eIF2.
• Genome-wide ribosome profiling to assess the impact of SFSV NSs on cellular translation during ISR activation.
• Introduction of SFSV NSs into primary neurons and iPS cell-derived motor neurons to evaluate neuroprotective effects.

Main Results:

• Cryo-EM revealed that SFSV NSs binds to the eIF2B α-subunit, competitively inhibiting eIF2(αP) binding and preserving eIF2B's nucleotide exchange activity.
• Ribosome profiling demonstrated that SFSV NSs attenuates the ISR in human cells stressed by thapsigargin.
• SFSV NSs conferred neuroprotection in rat hippocampal and human iPS cell-derived motor neurons subjected to ISR-inducing stress.

Conclusions:

• SFSV NSs directly interferes with the ISR pathway by stabilizing eIF2B function, thereby preventing translation shutdown during viral infection.
• The neuroprotective effects of SFSV NSs highlight its potential as a therapeutic agent for neurological disorders where ISR inhibition is beneficial.