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.
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
revised:
03
03
2023
received:
03
03
2023
accepted:
10
04
2023
medline:
31
8
2023
pubmed:
25
4
2023
entrez:
25
04
2023
Statut:
ppublish
Résumé
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. 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. 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. 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.
Substances chimiques
Caspase 8
EC 3.4.22.-
Galectin 3
0
Lysosomal Membrane Proteins
0
CASP8 protein, human
EC 3.4.22.-
Casp8 protein, mouse
EC 3.4.22.-
LAMP3 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1586-1598Subventions
Organisme : Intramural NIH HHS
ID : ZIA DE000695
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIG DE000740
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIC DE000750
Pays : United States
Informations de copyright
© 2023 American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
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