HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1
BackgroundKostmann 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 kno...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2025.1624718/full |
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| author | Keita Tanigaki Tsukasa Tamamori Naoko Sasaki Risako Matsumura Shunsuke Yamaga Akito Sakanaka Atsuo Amano Michiya Matsusaki Hiroki Takeuchi Masae Kuboniwa |
| author_facet | Keita Tanigaki Tsukasa Tamamori Naoko Sasaki Risako Matsumura Shunsuke Yamaga Akito Sakanaka Atsuo Amano Michiya Matsusaki Hiroki Takeuchi Masae Kuboniwa |
| author_sort | Keita Tanigaki |
| collection | DOAJ |
| description | BackgroundKostmann 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.ResultsExaminations 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.ConclusionThese 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. |
| format | Article |
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| institution | Kabale University |
| issn | 2296-634X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj-art-6157afee8c344589aeab4e736a962a6d2025-08-20T03:37:31ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2025-08-011310.3389/fcell.2025.16247181624718HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1Keita Tanigaki0Tsukasa Tamamori1Naoko Sasaki2Risako Matsumura3Shunsuke Yamaga4Akito Sakanaka5Atsuo Amano6Michiya Matsusaki7Hiroki Takeuchi8Masae Kuboniwa9Department of Preventive Dentistry, Graduate School of Dentistry, The Osaka University, Osaka, JapanDepartment of Preventive Dentistry, Graduate School of Dentistry, The Osaka University, Osaka, JapanJoint Research Laboratory (TOPPAN) for Advanced Cell Regulatory Chemistry, Graduate School of Engineering, The Osaka University, Osaka, JapanDepartment of Preventive Dentistry, Graduate School of Dentistry, The Osaka University, Osaka, JapanDepartment of Preventive Dentistry, The Osaka University Dental Hospital, Osaka, JapanDepartment of Preventive Dentistry, Graduate School of Dentistry, The Osaka University, Osaka, JapanDepartment of Preventive Dentistry, Graduate School of Dentistry, The Osaka University, Osaka, JapanDepartment of Applied Chemistry, Graduate School of Engineering, The Osaka University, Osaka, JapanDepartment of Preventive Dentistry, The Osaka University Dental Hospital, Osaka, JapanDepartment of Preventive Dentistry, Graduate School of Dentistry, The Osaka University, Osaka, JapanBackgroundKostmann 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.ResultsExaminations 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.ConclusionThese 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.https://www.frontiersin.org/articles/10.3389/fcell.2025.1624718/fullHAX1JAM1Kostmann syndromecisplatinperiodontitisbarrier |
| spellingShingle | Keita Tanigaki Tsukasa Tamamori Naoko Sasaki Risako Matsumura Shunsuke Yamaga Akito Sakanaka Atsuo Amano Michiya Matsusaki Hiroki Takeuchi Masae Kuboniwa HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1 Frontiers in Cell and Developmental Biology HAX1 JAM1 Kostmann syndrome cisplatin periodontitis barrier |
| title | HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1 |
| title_full | HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1 |
| title_fullStr | HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1 |
| title_full_unstemmed | HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1 |
| title_short | HAX1, gene responsible for Kostmann syndrome, regulates gingival epithelial barrier function via intracellular trafficking of JAM1 |
| title_sort | hax1 gene responsible for kostmann syndrome regulates gingival epithelial barrier function via intracellular trafficking of jam1 |
| topic | HAX1 JAM1 Kostmann syndrome cisplatin periodontitis barrier |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2025.1624718/full |
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