Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/ijms22041630
Keywords
Sjö gren’ s syndrome; Cathepsin S; Rab27a; lacrimal gland; rab proteins; acinar cells; regulated secretion; endolysosomal secretion
Funding
- NIH [EY011386, P30EY029220]
- Research to Prevent Blindness (RPB), New York, NY
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The study revealed that Rab27a is involved in the secretion of CTSS in lacrimal gland acinar cells through the regulated pathway of fusion and depletion of CTSS-enriched vesicles, as well as through a novel endolysosomal pathway increased in Sjogren's syndrome.
Altered lacrimal gland (LG) secretion is a feature of autoimmune dacryoadenitis in Sjogren's syndrome (SS). Cathepsin S (CTSS) is increased in tears of SS patients, which may contribute to disease. Rab3D and Rab27a/b isoforms are effectors of exocytosis in LG, but Rab27a is poorly studied. To investigate whether Rab27a mediates CTSS secretion, we utilized quantitative confocal fluorescence microscopy of LG from SS-model male NOD and control male BALB/c mice, showing that Rab27a-enriched vesicles containing CTSS were increased in NOD mouse LG. Live-cell imaging of cultured lacrimal gland acinar cells (LGAC) transduced with adenovirus encoding wild-type (WT) mCFP-Rab27a revealed carbachol-stimulated fusion and depletion of mCFP-Rab27a-enriched vesicles. LGAC transduced with dominant-negative (DN) mCFP-Rab27a exhibited significantly reduced carbachol-stimulated CTSS secretion by 0.5-fold and beta-hexosaminidase by 0.3-fold, relative to stimulated LGAC transduced with WT mCFP-Rab27a. Colocalization of Rab27a and endolysosomal markers (Rab7, Lamp2) with the apical membrane was increased in both stimulated BALB/c and NOD mouse LG, but the extent of colocalization was much greater in NOD mouse LG. Following stimulation, Rab27a colocalization with endolysosomal membranes was decreased. In conclusion, Rab27a participates in CTSS secretion in LGAC though the major regulated pathway, and through a novel endolysosomal pathway that is increased in SS.
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