title: Imbalanced Rab3D versus Rab27 increases cathepsin S secretion from lacrimal acini in a mouse model of Sjögren's Syndrome.
abstract: The mechanism responsible for the altered spectrum of tear proteins secreted by lacrimal gland acinar cells (LGAC) in patients with Sjögren's Syndrome (SS) remains unknown. We have previously identified increased cathepsin S (CTSS) activity as a unique characteristic of tears of patients with SS. Here, we investigated the role of Rab3D, Rab27a, and Rab27b proteins in the enhanced release of CTSS from LGAC. Similar to patients with SS and to the male nonobese diabetic (NOD) mouse model of SS, CTSS activity was elevated in tears of mice lacking Rab3D. Findings of lower gene expression and altered localization of Rab3D in NOD LGAC reinforce a role for Rab3D in suppressing excess CTSS release under physiological conditions. However, CTSS activity was significantly reduced in tears of mice lacking Rab27 isoforms. The reliance of CTSS secretion on Rab27 activity was supported by in vitro findings that newly synthesized CTSS was detected in and secreted from Rab27-enriched secretory vesicles and that expression of dominant negative Rab27b reduced carbachol-stimulated secretion of CTSS in cultured LGAC. High-resolution 3D-structured illumination microscopy revealed microdomains of Rab3D and Rab27 isoforms on the same secretory vesicles but present in different proportions on different vesicles, suggesting that changes in their relative association with secretory vesicles may tailor the vesicle contents. We propose that a loss of Rab3D from secretory vesicles, leading to disproportionate Rab27-to-Rab3D activity, may contribute to the enhanced release of CTSS in tears of patients with SS.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California;
authors.forename: Zhen
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California;
authors.forename: Maria C
authors.initials: MC
authors.lastname: Edman
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California;
authors.forename: Pang-Yu
authors.initials: PY
authors.lastname: Hsueh
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California;
authors.forename: Chiao-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California;
authors.forename: Wannita
authors.initials: W
authors.lastname: Klinngam
authors.affiliation: Imperial College London, London, United Kingdom.
authors.forename: Tanya
authors.initials: T
authors.lastname: Tolmachova
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California;
authors.forename: Curtis T
authors.initials: CT
authors.lastname: Okamoto
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California; Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California; shalvar@usc.edu.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Hamm-Alvarez
mesh_terms: D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005838:Genotype; D007765:Lacrimal Apparatus / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D021962:Membrane Microdomains / Q000201:enzymology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010641:Phenotype; D011817:Rabbits; D022142:Secretory Vesicles / Q000201:enzymology; D012859:Sjogren's Syndrome / Q000201:enzymology* / Q000235:genetics; D013666:Tears / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000075745:rab27 GTP-Binding Proteins; D020692:rab3 GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000075745:rab27 GTP-Binding Proteins; D002217:Carbachol; D002403:Cathepsins; C028217:cathepsin S; C512958:Rab27b protein, mouse; C116711:Rab3d protein, mouse; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins; D020692:rab3 GTP-Binding Proteins
keywords: Rab; Sjögren's Syndrome; exocytosis; lacrimal gland; lysosomal protease; tears