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; Kawabe, Yuya; Yamashita, Tomoko; Omi, Tsubasa; Nagata, Kenichi; Tagami, Shinji; Nagai, Yoshitaka; Ikeda, Manabu

doi:https://doi.org/10.1016/j.jbc.2024.105703

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

アクセス数:590件（2025-06-26 14:03 集計）

固定URL: https://hdl.handle.net/11094/95671

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タイトル	eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS
著者	著者名 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 著者名 Mori, Kohji
	著者名 Fujino, Yuzo
	著者名 Kawabe, Yuya
	著者名 Yamashita, Tomoko
	NRID 1000000752122 1000000752122 著者名 Omi, Tsubasa
	著者名 Nagata, Kenichi
	NRID 1000040362735 1000040362735 researchmap permalink tagami1221 tagami1221 Scopus Author ID 7003308602 7003308602 著者名 Tagami, Shinji
	NRID 1000060335354 1000060335354 著者名 Nagai, Yoshitaka
	NRID 1000060284395 1000060284395 researchmap permalink manabu_ikeda manabu_ikeda Scopus Author ID 7404692889 7404692889 著者名 Ikeda, Manabu
キーワード等	C9orf72
	DPR
	eIF5
	FTLD
	RAN translation
内容	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.
抄録	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.
出版者	American Society for Biochemistry and Molecular Biology Inc.
収録物名	Journal of Biological Chemistry
巻(号)	300(3)
ページ	105703
刊行年月	2024-03-01
言語	英語
ハンドルURL	https://hdl.handle.net/11094/95671
PISSN	00219258
eISSN	1083351X
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1016/j.jbc.2024.105703
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	text
DCTERMS.bibliographicCitation	Journal of Biological Chemistry. 2024, 300(3), p. 105703
DC.title	eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS
DC.creator	Gotoh, Shiho
	Mori, Kohji
	Fujino, Yuzo
	Kawabe, Yuya
	Yamashita, Tomoko
	Omi, Tsubasa
	Nagata, Kenichi
	Tagami, Shinji
	Nagai, Yoshitaka
	Ikeda, Manabu
DC.publisher	American Society for Biochemistry and Molecular Biology Inc.
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-03-01
DC.identifier	https://doi.org/10.1016/j.jbc.2024.105703
DC.subject	C9orf72
	DPR
	eIF5
	FTLD
	RAN translation
DC.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.
DCTERMS.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.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
DC.format	95671
citation_title	eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS
citation_author	Gotoh, Shiho
	Mori, Kohji
	Fujino, Yuzo
	Kawabe, Yuya
	Yamashita, Tomoko
	Omi, Tsubasa
	Nagata, Kenichi
	Tagami, Shinji
	Nagai, Yoshitaka
	Ikeda, Manabu
citation_publisher	American Society for Biochemistry and Molecular Biology Inc.
citation_language	英語
citation_date	2024-03-01
citation_journal_title	Journal of Biological Chemistry
citation_volume	300
citation_issue	3
citation_firstpage	105703
citation_doi	https://doi.org/10.1016/j.jbc.2024.105703
citation_public_url	https://hdl.handle.net/11094/95671

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

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