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

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

Research output: Contribution to journal › Article › peer-review

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 [Stim1/2^K14Cre(+⁾] in salivary glands exhibited reduced Ca²⁺ levels and hyposalivate. SOCE was functionally required for the activation of the Ca²⁺ activated Cl− channel ANO1. Ageing Stim1/2^K14Cre(+⁾ 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.

Original language	English (US)
Article number	zqae047
Journal	Function
Volume	6
Issue number	1
DOIs	https://doi.org/10.1093/function/zqae047
State	Published - 2025

Keywords

ANO1
STIM1
Sjogren’s disease
calcium signaling
hyposalivation
tool-like receptors

ASJC Scopus subject areas

Physiology
Molecular Medicine
Cell Biology
Cancer Research

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title = "Loss of STIM1 and STIM2 in Salivary Glands Disrupts ANO1 Function but Does Not Induce Sjogren{\textquoteright}s Disease",

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{\textquoteright}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{\textquoteright}s disease, calcium signaling, hyposalivation, tool-like receptors",

author = "Son, {Ga Yeon} and Anna Zou and Amanda Wahl and Huang, {Kai Ting} and Saruul Zorgit and Manikandan Vinu and Fang Zhou and Larry Wagner and Youssef Idaghdour and Yule, {David I.} and Stefan Feske and Lacruz, {Rodrigo S.}",

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year = "2025",

doi = "10.1093/function/zqae047",

language = "English (US)",

volume = "6",

journal = "Function",

issn = "2633-8823",

publisher = "Oxford University Press",

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T1 - Loss of STIM1 and STIM2 in Salivary Glands Disrupts ANO1 Function but Does Not Induce Sjogren’s Disease

AU - Son, Ga Yeon

AU - Zou, Anna

AU - Wahl, Amanda

AU - Huang, Kai Ting

AU - Zorgit, Saruul

AU - Vinu, Manikandan

AU - Zhou, Fang

AU - Wagner, Larry

AU - Idaghdour, Youssef

AU - Yule, David I.

AU - Feske, Stefan

AU - Lacruz, Rodrigo S.

N1 - Publisher Copyright: © The Author(s) 2024. Published by Oxford University Press on behalf of American Physiological Society.

PY - 2025

Y1 - 2025

N2 - 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.

AB - 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.

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Loss of STIM1 and STIM2 in Salivary Glands Disrupts ANO1 Function but Does Not Induce Sjogren’s Disease

Abstract

Keywords

ASJC Scopus subject areas

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