VPS13B, gene responsible for Cohen syndrome, regulates gingival epithelial barrier function via intracellular trafficking of coxsackievirus and adenovirus receptor

TL;DR

This study shows that the VPS13B gene, linked to Cohen syndrome, helps protect the mouth's tissue barrier by controlling the movement of a receptor involved in fighting bacteria.

Contribution

The study reveals a novel role of VPS13B in intracellular trafficking of CXADR to maintain gingival epithelial barrier function.

Findings

Loss of VPS13B reduces cell surface localization of CXADR but not JAM1.

VPS13B knockout increases permeability to LPS and PGN, which is restored by CXADR-JAM1c−term expression.

VPS13B regulates intracellular trafficking of CXADR, providing a molecular basis for periodontal complications in Cohen syndrome.

Abstract

Cohen syndrome is an autosomal recessive genetic disease caused by mutations in the vacuolar protein sorting homolog B (VPS13B) gene that leads to a variety of complications including periodontitis. However, the molecular mechanism underlying periodontal inflammation caused by VPS13B dysfunction in human gingival epithelial cells remains unclear. A previous report noted that coxsackievirus and adenovirus receptor (CXADR) and junctional adhesion molecule 1 (JAM1) are involved in barrier functions against penetration by lipopolysaccharide (LPS) and peptidoglycan (PGN) into gingival tissues. The present study was conducted to examine the effects and significance of VPS13B on gingival barrier function. It was confirmed that loss of VPS13B resulted in decreased cell surface localization of CXADR, but not of JAM1. Additionally, abundant lysosomal localization of CXADR was detected in VPS13B-knockout cells followed treatment with bafilomycin A1, an inhibitor of lysosomal degradation. Other findings indicated that cell-surface localization of the CXADR-chimeric protein, in which C-terminus was exchanged with JAM1, was not disturbed by VPS13B knockout. Finally, VPS13B knockout led to greater permeability of gingival epithelial cell layers and tissues to LPS and PGN, which was restored by increased expression of CXADR-JAM1c−term. Together, these results show that VPS13B is involved in intracellular trafficking of CXADR as well as the barrier function of human gingival epithelial tissues, and thus indicate the molecular basis for periodontal complications in patients affected by Cohen syndrome.

The online version contains supplementary material available at 10.1038/s41598-026-40840-9.

Figures