{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T02:47:37Z","timestamp":1792032457662,"version":"4.4.0"},"reference-count":44,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T00:00:00Z","timestamp":1690416000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["ZIC\u2010DE\u2010000750\u201001"],"award-info":[{"award-number":["ZIC\u2010DE\u2010000750\u201001"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["ZIC\u2010DE\u2010000740\u201005"],"award-info":[{"award-number":["ZIC\u2010DE\u2010000740\u201005"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["1ZIADE000695"],"award-info":[{"award-number":["1ZIADE000695"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Lysosome\u2010associated membrane protein 3 (LAMP3) overexpression is implicated in the development and progression of Sj\u00f6gren'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\u2010induced lysosome\u2010dependent cell death and to test lysosomal biogenesis as a therapeutic intervention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human labial minor salivary gland biopsies were analyzed using immunofluorescence staining for LAMP3 expression levels and galectin\u20103 puncta formation, a marker of LMP. Expression level of caspase 8, an initiator of LMP, was determined by Western blotting in cell culture. Galectin\u20103 puncta formation and apoptosis were evaluated in cell cultures and a mouse model treated with glucagon\u2010like peptide 1 receptor (GLP\u20101R) agonists, a known promoter of lysosomal biogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Galectin\u20103 puncta formation was more frequent in the salivary glands of SjD patients compared to control glands. The proportion of galectin\u20103 puncta\u2013positive cells was positively correlated with LAMP3 expression levels in the glands. LAMP3 overexpression increased caspase 8 expression, and knockdown of caspase 8 decreased galectin\u20103 puncta formation and apoptosis in LAMP3\u2010overexpressing cells. Inhibition of autophagy increased caspase 8 expression, while restoration of lysosomal function using GLP\u20101R agonists decreased caspase 8 expression, which reduced galectin\u20103 puncta formation and apoptosis in both LAMP3\u2010overexpressing cells and mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>LAMP3 overexpression induced lysosomal dysfunction, resulting in lysosome\u2010dependent cell death via impaired autophagic caspase 8 degradation, and restoring lysosomal function using GLP\u20101R agonists could prevent this. These findings suggested that LAMP3\u2010induced lysosomal dysfunction is central to disease development and is a target for therapeutic intervention in SjD.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42540-toc-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  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