HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1

Tanigaki, Keita; Tamamori, Tsukasa; Sasaki, Naoko; Matsumura, Risako; Yamaga, Shunsuke; Sakanaka, Akito; Amano, Atsuo; Matsusaki, Michiya; Takeuchi, Hiroki; Kuboniwa, Masae

doi:https://doi.org/10.3389/fcell.2025.1624718

HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1

Tanigaki, Keita; Tamamori, Tsukasa; Sasaki, Naoko et al.

Frontiers in Cell and Developmental Biology, 2025, 13, 1624718

アクセス数:155件（2026-02-16 00:54 集計）

固定URL: https://hdl.handle.net/11094/103504

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タイトル	HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1
著者	NRID 1000071004652 1000071004652 著者名 Tanigaki, Keita
	著者名 Tamamori, Tsukasa
	NRID 1000010388762 1000010388762 著者名 Sasaki, Naoko
	著者名 Matsumura, Risako
	NRID 1000050964863 1000050964863 ORCID 0009-0000-1861-659X 0009-0000-1861-659X Scopus Author ID 57822438200 57822438200 著者名 Yamaga, Shunsuke
	NRID 1000090815557 1000090815557 ORCID 0000-0001-9733-6886 0000-0001-9733-6886 researchmap permalink sknk1022 sknk1022 Scopus Author ID 56814868300 56814868300 著者名 Sakanaka, Akito
	NRID 1000050193024 1000050193024 ORCID 0000-0002-5158-147X 0000-0002-5158-147X researchmap permalink read0014208 read0014208 Scopus Author ID 7101649822 7101649822 著者名 Amano, Atsuo
	NRID 1000000419467 1000000419467 ORCID 0000-0003-4294-9313 0000-0003-4294-9313 researchmap permalink read0093431 read0093431 Scopus Author ID 6701561701 6701561701 著者名 Matsusaki, Michiya
	NRID 1000040572186 1000040572186 ORCID 0000-0001-5938-1897 0000-0001-5938-1897 researchmap permalink takeuchih takeuchih Scopus Author ID 55007392300 55007392300 著者名 Takeuchi, Hiroki
	NRID 1000000303983 1000000303983 ORCID 0000-0002-3332-2431 0000-0002-3332-2431 researchmap permalink MasaeKuboniwa_URL MasaeKuboniwa_URL Scopus Author ID 56089471500 56089471500 著者名 Kuboniwa, Masae
キーワード等	anticancer drug
	barrier
	cisplatin
	HAX1
	JAM1
	Kostmann syndrome
	periodontitis
	Porphyromonas gingivalis
内容	Tanigaki K., Tamamori T., Sasaki N., et al. HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1. Frontiers in Cell and Developmental Biology 13, 1624718 (2025); https://doi.org/10.3389/fcell.2025.1624718.
抄録	Background: Kostmann syndrome is an autosomal recessive disorder caused by a mutation of the hematopoietic cell-specific Lyn substrate 1 associated protein X-1 (HAX1) gene, and characterized by low number of neutrophils and increased susceptibility to infections. Additionally, Kostmann syndrome is known to be complicated by periodontitis, though the etiological molecular basis remains unclear. We previously reported findings showing that junctional adhesion molecule 1 (JAM1), a tight junction-associated protein, has an important role to maintain epithelial barrier function in gingival tissues, which prevents penetration of bacterial virulence factors, such as lipopolysaccharide (LPS) and peptidoglycan (PGN). In the present study, the effects of HAX1 on gingival barrier function were investigated. Results: Examinations of immortalized human gingival epithelial (IHGE) cells showed HAX1 localization in mitochondria. In HAX1-knockdown IHGE cells, significantly decreased levels of JAM1 were found. Additionally, cisplatin, a chemotherapeutic agent reported to inhibit HAX1, also led to decreased expression of both HAX1 and JAM1. Furthermore, JAM1 was scarcely detected in HAX1-knockout cells, while administration of bafilomycin A1, a lysosomal inhibitor, restored JAM1 expression in those cells. Finally, using a three-dimensional multilayered gingival epithelial tissue model, HAX1 knockout along with cisplatin administration was also found to increase permeability to LPS and PGN, which was dependent on JAM1 expression. Conclusion: These results indicate that periodontal diseases complicated with Kostmann syndrome are induced by reduced JAM1 expression, caused by JAM1 being missorted into lysosomes by HAX1 dysfunction.
出版者	Frontiers Media SA
収録物名	Frontiers in Cell and Developmental Biology
巻(号)	13
ページ	1624718
刊行年月	2025-08-13
言語	英語
ハンドルURL	https://hdl.handle.net/11094/103504
eISSN	2296634X
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.3389/fcell.2025.1624718
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	Frontiers in Cell and Developmental Biology. 2025, 13, p. 1624718
DC.title	HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1
DC.creator	Tanigaki, Keita
	Tamamori, Tsukasa
	Sasaki, Naoko
	Matsumura, Risako
	Yamaga, Shunsuke
	Sakanaka, Akito
	Amano, Atsuo
	Matsusaki, Michiya
	Takeuchi, Hiroki
	Kuboniwa, Masae
DC.publisher	Frontiers Media SA
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-08-13
DC.identifier	https://doi.org/10.3389/fcell.2025.1624718
DC.subject	anticancer drug
	barrier
	cisplatin
	HAX1
	JAM1
	Kostmann syndrome
	periodontitis
	Porphyromonas gingivalis
DC.description	Tanigaki K., Tamamori T., Sasaki N., et al. HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1. Frontiers in Cell and Developmental Biology 13, 1624718 (2025); https://doi.org/10.3389/fcell.2025.1624718.
DCTERMS.abstract	Background: Kostmann syndrome is an autosomal recessive disorder caused by a mutation of the hematopoietic cell-specific Lyn substrate 1 associated protein X-1 (HAX1) gene, and characterized by low number of neutrophils and increased susceptibility to infections. Additionally, Kostmann syndrome is known to be complicated by periodontitis, though the etiological molecular basis remains unclear. We previously reported findings showing that junctional adhesion molecule 1 (JAM1), a tight junction-associated protein, has an important role to maintain epithelial barrier function in gingival tissues, which prevents penetration of bacterial virulence factors, such as lipopolysaccharide (LPS) and peptidoglycan (PGN). In the present study, the effects of HAX1 on gingival barrier function were investigated. Results: Examinations of immortalized human gingival epithelial (IHGE) cells showed HAX1 localization in mitochondria. In HAX1-knockdown IHGE cells, significantly decreased levels of JAM1 were found. Additionally, cisplatin, a chemotherapeutic agent reported to inhibit HAX1, also led to decreased expression of both HAX1 and JAM1. Furthermore, JAM1 was scarcely detected in HAX1-knockout cells, while administration of bafilomycin A1, a lysosomal inhibitor, restored JAM1 expression in those cells. Finally, using a three-dimensional multilayered gingival epithelial tissue model, HAX1 knockout along with cisplatin administration was also found to increase permeability to LPS and PGN, which was dependent on JAM1 expression. Conclusion: These results indicate that periodontal diseases complicated with Kostmann syndrome are induced by reduced JAM1 expression, caused by JAM1 being missorted into lysosomes by HAX1 dysfunction.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	103504
citation_title	HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1
citation_author	Tanigaki, Keita
	Tamamori, Tsukasa
	Sasaki, Naoko
	Matsumura, Risako
	Yamaga, Shunsuke
	Sakanaka, Akito
	Amano, Atsuo
	Matsusaki, Michiya
	Takeuchi, Hiroki
	Kuboniwa, Masae
citation_publisher	Frontiers Media SA
citation_language	英語
citation_date	2025-08-13
citation_journal_title	Frontiers in Cell and Developmental Biology
citation_volume	13
citation_firstpage	1624718
citation_doi	https://doi.org/10.3389/fcell.2025.1624718
citation_public_url	https://hdl.handle.net/11094/103504

HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1

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