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

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.

eIF3 mRNA selectivity profiling reveals eIF3k as a cancer-relevant regulator of ribosome content

“…Likewise, eIF3f was shown to advance sperm-specific translation through interaction with proteins that bind MIWI/piRNAs in 3’-UTRs thus leading to circularization of mRNA which is thought to promote translation (Dai et al, 2019). Even more recently, eIF3g was implicated in neuron-specific translation in C. elegans (Blazie et al, 2021). Furthermore, eIF3c was shown to be dispensable for global translation and viability in mice but to direct the translation of the Sonic Hedgehog receptor PTCH1 through a pyrimidine-rich motif in the 5’-UTR (Fujii et al, 2021).…”