Lysosome‐Associated Membrane Protein 3 Induces Lysosome‐Dependent Cell Death by Impairing Autophagic Caspase 8 Degradation in the Salivary Glands of Individuals With Sjögren's Disease

Objective Lysosome‐associated membrane protein 3 (LAMP3) overexpression is implicated in the development and progression of Sjögren's disease (SjD) by inducing lysosomal membrane permeabilization (LMP) and apoptotic cell death in salivary gland epithelium. The aim of this study was to clarify the molecular details of LAMP3‐induced lysosome‐dependent cell death and to test lysosomal biogenesis as a therapeutic intervention. Methods Human labial minor salivary gland biopsies were analyzed using immunofluorescence staining for LAMP3 expression levels and galectin‐3 puncta formation, a marker of LMP. Expression level of caspase 8, an initiator of LMP, was determined by Western blotting in cell culture. Galectin‐3 puncta formation and apoptosis were evaluated in cell cultures and a mouse model treated with glucagon‐like peptide 1 receptor (GLP‐1R) agonists, a known promoter of lysosomal biogenesis. Results Galectin‐3 puncta formation was more frequent in the salivary glands of SjD patients compared to control glands. The proportion of galectin‐3 puncta–positive cells was positively correlated with LAMP3 expression levels in the glands. LAMP3 overexpression increased caspase 8 expression, and knockdown of caspase 8 decreased galectin‐3 puncta formation and apoptosis in LAMP3‐overexpressing cells. Inhibition of autophagy increased caspase 8 expression, while restoration of lysosomal function using GLP‐1R agonists decreased caspase 8 expression, which reduced galectin‐3 puncta formation and apoptosis in both LAMP3‐overexpressing cells and mice. Conclusion LAMP3 overexpression induced lysosomal dysfunction, resulting in lysosome‐dependent cell death via impaired autophagic caspase 8 degradation, and restoring lysosomal function using GLP‐1R agonists could prevent this. These findings suggested that LAMP3‐induced lysosomal dysfunction is central to disease development and is a target for therapeutic intervention in SjD. image