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

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Abstract

The translation initiation complex eIF3 imparts specialized functions to regulate protein expression. However, understanding of eIF3 activities in neurons remains limited despite widespread dysregulation of eIF3 subunits in neurological disorders. Here, we report a selective role of the C. elegans RNA-binding subunit EIF-3.G in shaping the neuronal protein landscape. We identify a missense mutation in the conserved Zinc-Finger (ZF) of EIF-3.G that acts in a gain-of-function manner to dampen neuronal hyperexcitation. Using neuron type-specific seCLIP, we systematically mapped EIF-3.G-mRNA interactions and identified EIF-3.G occupancy on GC-rich 5′UTRs of a select set of mRNAs enriched in activity-dependent functions. We demonstrate that the ZF mutation in EIF-3.G alters translation in a 5′UTR dependent manner. Our study reveals an in vivo mechanism for eIF3 in governing neuronal protein levels to control neuronal activity states and offers insights into how eIF3 dysregulation contributes to neuronal disorders.

Data availability

Raw and processed seCLIP datasets from this study have been uploaded to the Gene Expression Omnibus (GEO) under accession number GSE152704.

The following data sets were generated

(2021) seCLIP of C. elegans EIF-3.G in the cholinergic motor neurons
NCBI Gene Expression Omnibus, GSE152704.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE152704

The following previously published data sets were used

(2019) Neuronal transcriptome analyses reveal novel neuropeptide modulators of excitation and inhibition imbalance in C. elegans
GSE139212.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE139212

Article and author information

Author details

Stephen M Blazie

Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.
Seika Takayanagi-Kiya

Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.
Katherine M McCulloch

Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.
Yishi Jin

Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, United States

For correspondence
yijin@ucsd.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9371-9860

Funding

National Institute of Health (NS R37 035546)

Yishi Jin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.