Eukaryotic initiation factor EIF-3.G augments mRNA translation efficiency to regulate neuronal activity.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• The translation initiation complex eukaryotic translation initiation factor 3 (eIF3) plays a crucial role in regulating protein expression.
• While eIF3 subunits are implicated in neurological disorders, their specific functions in neurons are not well understood.
• Understanding eIF3's role in neuronal activity is vital for addressing neurological diseases.

Purpose of the Study:

• To investigate the specific role of the RNA-binding subunit EIF-3.G from the eukaryotic translation initiation factor 3 (eIF3) complex in shaping the neuronal proteome.
• To explore the mechanism by which a gain-of-function mutation in EIF-3.G's Zinc-Finger (ZF) domain affects neuronal excitability.

Main Methods:

• Utilized *C. elegans* as a model organism.
• Employed neuron-type-specific single-cell crosslinking immunoprecipitation and sequencing (seCLIP) to map EIF-3.G-mRNA interactions.
• Analyzed the impact of an EIF-3.G ZF mutation on mRNA translation, focusing on 5' untranslated regions (5'UTRs).

Main Results:

• Identified a missense mutation in the conserved Zinc-Finger (ZF) of EIF-3.G that confers a gain-of-function, reducing neuronal hyperexcitation.
• Systematically mapped EIF-3.G-mRNA interactions, revealing its binding to GC-rich 5'UTRs of mRNAs involved in activity-dependent neuronal functions.
• Demonstrated that the ZF mutation alters translation in a 5'UTR-dependent manner, impacting neuronal protein levels.

Conclusions:

• Established a novel in vivo mechanism where eIF3, specifically the EIF-3.G subunit, governs neuronal protein synthesis to modulate neuronal activity.
• Highlighted the significance of EIF-3.G's RNA-binding activity and its ZF domain in regulating neuronal function.
• Provided insights into how dysregulation of eIF3 subunits can contribute to the pathophysiology of neurological disorders.