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Impaired GATE16-mediated exocytosis in exocrine tissues causes Sjögren’s syndrome-like exocrinopathy

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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.

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The data that support the findings in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the Integrated Microscopy Core of Baylor College of Medicine, UTHealth Flow Cytometry Service Center for flow cytometry, and The High-Resolution Electron Microscopy Facility of the UT MD Anderson Cancer Center for technical assistance.

Funding

This study was supported by grants from the National Institute of Dental and Craniofacial Research (DE026767 to JI) and UTHealth School of Dentistry faculty funding to JI.

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Authors and Affiliations

  1. Department of Diagnostic & Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX, 77054, USA

    Akiko Suzuki, Chihiro Iwaya, Kenichi Ogata, Hiroki Yoshioka, Junbo Shim & Junichi Iwata

  2. Center for Craniofacial Research, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX, 77054, USA

    Akiko Suzuki, Chihiro Iwaya, Kenichi Ogata, Hiroki Yoshioka, Junbo Shim & Junichi Iwata

  3. Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo, 113-8431, Japan

    Isei Tanida

  4. Department of Organ and Cell Physiology, Juntendo University Graduate School of Medicine, Tokyo, 113-8431, Japan

    Masaaki Komatsu

  5. Division of Genome Research, Research Institute for Diseases of Old Ages, Juntendo University School of Medicine, Tokyo, 113-8431, Japan

    Norihiro Tada

  6. Pediatric Research Center, School of Medicine, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    Junichi Iwata

  7. MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA

    Junichi Iwata

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  1. Akiko Suzuki
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Contributions

AS and JI designed research; AS, CI, KO, HY, JS, and JI performed research; AS, IT, MK, NT, and JI contributed to generate new mouse models; AS, CI, KO, HY, and JI analyzed data; and AS and JI wrote the paper.

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Correspondence to Junichi Iwata.

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Suzuki, A., Iwaya, C., Ogata, K. et al. Impaired GATE16-mediated exocytosis in exocrine tissues causes Sjögren’s syndrome-like exocrinopathy. Cell. Mol. Life Sci. 79, 307 (2022). https://doi.org/10.1007/s00018-022-04334-x

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