ER Stress Ire1-Xbp1s Pathway Maintains Youthful Epidermal Basal Layer Through the Regulation of Cell Proliferation

Semmy, Daniel; Abe, Kota; Honda, Mizuki; Omori, Hiroko; Ogamino, Shohei; Mercurio, Tobias Clausen; Asakawa, Kyosuke; Nishimura, Emi K.; Oki, Shinya; Ohkawa, Yasuyuki; Ishitani, Tohru

doi:https://doi.org/10.1111/acel.70258

ER Stress Ire1-Xbp1s Pathway Maintains Youthful Epidermal Basal Layer Through the Regulation of Cell Proliferation

Semmy, Daniel; Abe, Kota; Honda, Mizuki et al.

Aging Cell, 2025

アクセス数:241件（2026-02-15 21:10 集計）

固定URL: https://hdl.handle.net/11094/103283

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タイトル	ER Stress Ire1-Xbp1s Pathway Maintains Youthful Epidermal Basal Layer Through the Regulation of Cell Proliferation
著者	著者名 Semmy, Daniel
	NRID 1000010867279 1000010867279 ORCID 0009-0003-5835-5867 0009-0003-5835-5867 researchmap permalink koa koa Scopus Author ID 57219409573 57219409573 著者名 Abe, Kota
	NRID 1000050828978 1000050828978 著者名 Honda, Mizuki
	著者名 Omori, Hiroko
	NRID 1000071002200 1000071002200 ORCID 0000-0001-7562-3753 0000-0001-7562-3753 researchmap permalink ogamino_shohei ogamino_shohei 著者名 Ogamino, Shohei
	著者名 Mercurio, Tobias Clausen
	NRID 1000060747187 1000060747187 著者名 Asakawa, Kyosuke
	NRID 1000070396331 1000070396331 著者名 Nishimura, Emi K.
	NRID 1000090452713 1000090452713 著者名 Oki, Shinya
	NRID 1000080448430 1000080448430 著者名 Ohkawa, Yasuyuki
	NRID 1000040448428 1000040448428 ORCID 0000-0002-6200-7043 0000-0002-6200-7043 researchmap permalink read0148831 read0148831 Scopus Author ID 8079317200 8079317200 著者名 Ishitani, Tohru
キーワード等	cell proliferation
	endoplasmic reticulum stress
	Ire1 protein
	skin aging
	unfolded protein response
内容	Semmy D., Abe K., Honda M., et al. ER Stress Ire1-Xbp1s Pathway Maintains Youthful Epidermal Basal Layer Through the Regulation of Cell Proliferation. Aging Cell (2025); https://doi.org/10.1111/acel.70258.
抄録	The endoplasmic reticulum (ER) stress-response is an adaptive cellular mechanism activated by an accumulation of unfolded proteins within the ER. Although recent evidence shows that the ER stress-response is activated in aged tissues, and therefore ER stress is considered a candidate driver of aging, the spatiotemporal regulation and roles of the ER stress-response during aging remain unclear. To address this research gap, we introduced an Ire1-Xbp1s ER stress-response pathway-sensitive reporter into the ultra-short-lived vertebrate Nothobranchius furzeri that allows for the analysis of its aging processes within a short period of time. Using this reporter in N. furzeri, we confirmed the previously reported age-dependent activation of ER stress in various tissues and identified an unexpected role of the Ire1-Xbp1s ER stress-response pathway in regulating epidermal tissue homeostasis and aging. The Ire1-Xbp1s ER stress-response pathway is active in the young epidermal basal layer but declines with aging. Photo-isolation chemistry-based spatial transcriptomics and functional assays revealed that the Ire1-Xbp1s pathway maintains young epidermal cell proliferation by activating the cell cycle regulator Vcp, whereas the age-dependent decline in glucose metabolism reduces Ire1-Xbp1s activity, consequently downregulating cell proliferation. Collectively, our study elucidates a previously unidentified role of the ER stress-response in skin aging, which can offer insights into therapeutic targets for promoting healthy skin.
出版者	John Wiley and Sons Inc
収録物名	Aging Cell
刊行年月	2025-10-12
言語	英語
ハンドルURL	https://hdl.handle.net/11094/103283
PISSN	14749718
eISSN	14749726
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1111/acel.70258
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 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	Aging Cell. 2025
DC.title	ER Stress Ire1-Xbp1s Pathway Maintains Youthful Epidermal Basal Layer Through the Regulation of Cell Proliferation
DC.creator	Semmy, Daniel
	Abe, Kota
	Honda, Mizuki
	Omori, Hiroko
	Ogamino, Shohei
	Mercurio, Tobias Clausen
	Asakawa, Kyosuke
	Nishimura, Emi K.
	Oki, Shinya
	Ohkawa, Yasuyuki
	Ishitani, Tohru
DC.publisher	John Wiley and Sons Inc
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-10-12
DC.identifier	https://doi.org/10.1111/acel.70258
DC.subject	cell proliferation
	endoplasmic reticulum stress
	Ire1 protein
	skin aging
	unfolded protein response
DC.description	Semmy D., Abe K., Honda M., et al. ER Stress Ire1-Xbp1s Pathway Maintains Youthful Epidermal Basal Layer Through the Regulation of Cell Proliferation. Aging Cell (2025); https://doi.org/10.1111/acel.70258.
DCTERMS.abstract	The endoplasmic reticulum (ER) stress-response is an adaptive cellular mechanism activated by an accumulation of unfolded proteins within the ER. Although recent evidence shows that the ER stress-response is activated in aged tissues, and therefore ER stress is considered a candidate driver of aging, the spatiotemporal regulation and roles of the ER stress-response during aging remain unclear. To address this research gap, we introduced an Ire1-Xbp1s ER stress-response pathway-sensitive reporter into the ultra-short-lived vertebrate Nothobranchius furzeri that allows for the analysis of its aging processes within a short period of time. Using this reporter in N. furzeri, we confirmed the previously reported age-dependent activation of ER stress in various tissues and identified an unexpected role of the Ire1-Xbp1s ER stress-response pathway in regulating epidermal tissue homeostasis and aging. The Ire1-Xbp1s ER stress-response pathway is active in the young epidermal basal layer but declines with aging. Photo-isolation chemistry-based spatial transcriptomics and functional assays revealed that the Ire1-Xbp1s pathway maintains young epidermal cell proliferation by activating the cell cycle regulator Vcp, whereas the age-dependent decline in glucose metabolism reduces Ire1-Xbp1s activity, consequently downregulating cell proliferation. Collectively, our study elucidates a previously unidentified role of the ER stress-response in skin aging, which can offer insights into therapeutic targets for promoting healthy skin.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	103283
citation_title	ER Stress Ire1-Xbp1s Pathway Maintains Youthful Epidermal Basal Layer Through the Regulation of Cell Proliferation
citation_author	Semmy, Daniel
	Abe, Kota
	Honda, Mizuki
	Omori, Hiroko
	Ogamino, Shohei
	Mercurio, Tobias Clausen
	Asakawa, Kyosuke
	Nishimura, Emi K.
	Oki, Shinya
	Ohkawa, Yasuyuki
	Ishitani, Tohru
citation_publisher	John Wiley and Sons Inc
citation_language	英語
citation_date	2025-10-12
citation_journal_title	Aging Cell
citation_doi	https://doi.org/10.1111/acel.70258
citation_public_url	https://hdl.handle.net/11094/103283

ER Stress Ire1-Xbp1s Pathway Maintains Youthful Epidermal Basal Layer Through the Regulation of Cell Proliferation

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