Impaired GATE16-Mediated Exocytosis in Exocrine Tissues Causes Sjögren’s Syndrome-Like Exocrinopathy

Authors

Language

English

Publication Date

5-20-2022

Journal

Cellular and Molecular Life Sciences

DOI

10.1007/s00018-022-04334-x

PMID

35593968

PMCID

PMC11071900

PubMedCentral® Posted Date

5-20-2022

PubMedCentral® Full Text Version

Post-print

Abstract

Sjögren's syndrome (SjS) is a chronic autoimmune disease characterized by immune cell infiltration of the exocrine glands, mainly the salivary and lacrimal glands. Despite recent advances in the clinical and mechanistic characterization of the disease, its etiology remains largely unknown. Here, we report that mice with a deficiency for either Atg7 or Atg3, which are enzymes involved in the ubiquitin modification pathway, in the salivary glands exhibit a SjS-like phenotype, characterized by immune cell infiltration with autoantibody detection, acinar cell death, and dry mouth. Prior to the onset of the SjS-like phenotype in these null mice, we detected an accumulation of secretory vesicles in the acinar cells of the salivary glands and found that GATE16, an uncharacterized autophagy-related molecule activated by ATG7 (E1-like enzyme) and ATG3 (E2-like enzyme), was highly expressed in these cells. Notably, GATE16 was activated by isoproterenol, an exocytosis inducer, and localized on the secretory vesicles in the acinar cells of the salivary glands. Failure to activate GATE16 was correlated with exocytosis defects in the acinar cells of the salivary glands in Atg7 and Atg3 cKO mice. Taken together, our results show that GATE16 activation regulated by the autophagic machinery is crucial for exocytosis and that defects in this pathway cause SjS.

Keywords

Animals, Autoantibodies, Autoimmune Diseases, Disease Models, Animal, Exocytosis, Mice, Salivary Glands, Sjogren's Syndrome, Salivary glands, Exocytosis, GATE16, Secretory vesicle, Mouse model

Published Open-Access

yes

Recommended Citation

, "Impaired GATE16-Mediated Exocytosis in Exocrine Tissues Causes Sjögren’s Syndrome-Like Exocrinopathy" (2022). Faculty, Staff and Student Publications. 80.
https://digitalcommons.library.tmc.edu/uthdb_docs/80