eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS

Gotoh, Shiho; Mori, Kohji; Fujino, Yuzo et al.

Journal of Biological Chemistry, 2024, 300(3), 105703

Number of Access:1,069（2025-08-16 00:38 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/95671

Link to primary information 

File Format Terms of use Size Views Date.Available Description information
JBiolChem_300_3_105703 pdf None 2.47 MB 97 2024.05.23  
Creative Commons : Attribution - NonCommercial - NoDerivatives

Item Information

Output File Export EndNote Basic Export Mendeley

Title
eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS
Creator
CreatorName
Gotoh, Shiho
NRID
1000040775318 1000040775318
ORCID
0000-0003-2629-0723 0000-0003-2629-0723
researchmap permalink
kmori_psy kmori_psy
Scopus Author ID
55579363000 55579363000
CreatorName
Mori, Kohji
CreatorName
Fujino, Yuzo
CreatorName
Kawabe, Yuya
CreatorName
Yamashita, Tomoko
NRID
1000000752122 1000000752122
CreatorName
Omi, Tsubasa
CreatorName
Nagata, Kenichi
NRID
1000040362735 1000040362735
researchmap permalink
tagami1221 tagami1221
Scopus Author ID
7003308602 7003308602
CreatorName
Tagami, Shinji
NRID
1000060335354 1000060335354
CreatorName
Nagai, Yoshitaka
NRID
1000060284395 1000060284395
researchmap permalink
manabu_ikeda manabu_ikeda
Scopus Author ID
7404692889 7404692889
CreatorName
Ikeda, Manabu
Subject
C9orf72
DPR
eIF5
FTLD
RAN translation
Description
Gotoh S., Mori K., Fujino Y., et al. eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS. Journal of Biological Chemistry 300, 105703 (2024); https://doi.org/10.1016/j.jbc.2024.105703.
Abstract
Tandem GGGGCC repeat expansion in C9orf72 is a genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeats are translated into dipeptide repeat proteins via repeat-associated non-AUG (RAN) translation. However, the regulatory mechanism of RAN translation remains unclear. Here, we reveal a GTPase-activating protein, eukaryotic initiation factor 5 (eIF5), which allosterically facilitates the conversion of eIF2-bound GTP into GDP upon start codon recognition, as a novel modifier of C9orf72 RAN translation. Compared to global translation, eIF5, but not its inactive mutants, preferentially stimulates poly-GA RAN translation. RAN translation is increased during integrated stress response, but the stimulatory effect of eIF5 on poly-GA RAN translation was additive to the increase of RAN translation during integrated stress response, with no further increase in phosphorylated eIF2α. Moreover, an alteration of the CUG near cognate codon to CCG or AUG in the poly-GA reading frame abolished the stimulatory effects, indicating that eIF5 primarily acts through the CUG-dependent initiation. Lastly, in a Drosophila model of C9orf72 FTLD/ALS that expresses GGGGCC repeats in the eye, knockdown of endogenous eIF5 by two independent RNAi strains significantly reduced poly-GA expressions, confirming in vivo effect of eIF5 on poly-GA RAN translation. Together, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS.
Publisher
American Society for Biochemistry and Molecular Biology Inc.
Source Title
Journal of Biological Chemistry
Volume (Issue)
300(3)
Page
105703
Date of Issued
2024-03-01
Language
English
Handle URL
https://hdl.handle.net/11094/95671
PISSN
00219258
eISSN
1083351X
Relation.isIdenticalTo
DOI (Publisher Version)
https://doi.org/10.1016/j.jbc.2024.105703
Access Rights
open access
CopyRight
This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
oaire:version
Version of Record
Category
学術雑誌論文 Journal Article