Loss of STIM1 and STIM2 in salivary glands disrupts ANO1 function but does not induce Sjogren's disease

Ga-Yeon Son; Anna Zou; Amanda Wahl; Kai Ting Huang; Saruul Zorgit; Manikandan Vinu; Fang Zhou; Larry Wagner; Youssef Idaghdour; David I Yule; Stefan Feske; Rodrigo S Lacruz

doi:10.1093/function/zqae047

Loss of STIM1 and STIM2 in salivary glands disrupts ANO1 function but does not induce Sjogren's disease

Function (Oxf). 2024 Oct 30:zqae047. doi: 10.1093/function/zqae047. Online ahead of print.

Authors

Affiliations

¹ Department of Molecular Pathobiology, New York University College of Dentistry, New York, USA.
² Department of Pharmacology and Physiology, University of Rochester, Rochester, New York, USA.
³ Biology Program, Division of Science and Mathematics, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
⁴ Department of Pathology, New York University Grossman School of Medicine, New York, New York, USA.

PMID: 39479800
DOI: 10.1093/function/zqae047

Abstract

Ca2+ signaling via the store operated Ca2+ entry (SOCE) mediated by STIM1 and STIM2 proteins and the ORAI1 Ca2+ channel is important in saliva fluid secretion and has been associated with Sjogren's disease (SjD). However, there are no studies addressing STIM1/2 dysfunction in salivary glands or SjD in animal models. We report that mice lacking Stim1 and Stim2 (Stim1/2K14Cre(+)) in salivary glands exhibited reduced Ca2+ levels and hyposalivate. SOCE was functionally required for the activation of the Ca2+ activated Cl- channel ANO1. Ageing Stim1/2K14Cre(+) mice showed no evidence of lymphocytic infiltration or increased levels of autoantibodies characteristic of SjD, possibly associated with a downregulation of toll-like receptor 8 (Tlr8) expression. Salivary gland biopsies of SjD patients showed increased expression of STIM1 and TLR7/8. Our study shows that SOCE activates ANO1 function and fluid secretion in salivary glands and highlights a potential link between SOCE and TLR signaling in SjD.

Keywords: ANO1; STIM1; Sjogren's disease; calcium signaling; hyposalivation; tool-like receptors.