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

Author:

Nakamura Hiroyuki1ORCID,Tanaka Tsutomu1ORCID,Zheng Changyu1,Afione Sandra A.1,Warner Blake M.2ORCID,Noguchi Masayuki3,Atsumi Tatsuya4,Chiorini John A.1

Affiliation:

1. Adeno‐Associated Virus Biology Section, NIDCR, NIH Bethesda Maryland

2. Salivary Disorder Unit, NIDCR, NIH Bethesda Maryland

3. Division of Cancer Biology, Institute for Genetic Medicine Hokkaido University Sapporo Japan

4. Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine Hokkaido University Sapporo Japan

Abstract

ObjectiveLysosome‐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.MethodsHuman 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.ResultsGalectin‐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.ConclusionLAMP3 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

Funder

National Institute of Dental and Craniofacial Research

Takeda Science Foundation

Publisher

Wiley

Subject

Immunology,Rheumatology,Immunology and Allergy

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