Targeting the Ca2 + Sensor STIM1 by Exosomal Transfer of Ebv-miR-BART13-3p is Associated with Sjögren's Syndrome

Alessia Gallo,Shyh-Ing Jang,Hwei Ling Ong,Paola Perez,Mayank Tandon,Indu Ambudkar,Gabor Illei,Ilias Alevizos

doi:10.1016/j.ebiom.2016.06.041

Abstract

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease that is associated with inflammation and dysfunction of salivary and lacrimal glands. The molecular mechanism(s) underlying this exocrinopathy is not known, although the syndrome has been associated with viruses, such as the Epstein Barr Virus (EBV). We report herein that an EBV-specific microRNA (ebv-miR-BART13-3p) is significantly elevated in salivary glands (SGs) of pSS patients and we show that it targets stromal interacting molecule 1 (STIM1), a primary regulator of the store-operated Ca2+ entry (SOCE) pathway that is essential for SG function, leading to loss of SOCE and Ca2+-dependent activation of NFAT. Although EBV typically infects B cells and not salivary epithelial cells, ebv-miR-BART13-3p is present in both cell types in pSS SGs. Importantly, we further demonstrate that ebv-miR-BART13-3p can be transferred from B cells to salivary epithelial cells through exosomes and it recapitulates its functional effects on calcium signaling in a model system.

Highlights

Sjögren's syndrome (SS) is an autoimmune disease characterized by dysfunction and inflammation of the exocrine glands, such as the salivary and lacrimal glands, as well as features of systemic autoimmunity
In our previous study (Alevizos et al, 2011), we reported that ebvmiR-BART13-3p was differentially expressed in patient salivary glands (SGs), showing a greater than 22-fold increase, and the upregulation of this miRNA was validated using independent samples with quantitative real time PCR
These algorithms predicted the binding of ebv-miR-BART13-3p to three potential sites on stromal interacting molecule 1 (STIM1) mRNAs, two located in the 3′UTR and one in the coding sequence

Summary

Introduction

Sjögren's syndrome (SS) is an autoimmune disease characterized by dysfunction and inflammation of the exocrine glands, such as the salivary and lacrimal glands, as well as features of systemic autoimmunity. It was proposed that in genetically predisposed individuals, various environmental factors such as viral infections could cause aberrant epithelial cell activation that results in a protracted inflammatory response both locally in the affected glands and systemically (Nikolov and Illei, 2009). The histological hallmark of SS is periductal inflammatory infiltration, which can vary from mild to diffuse (Nikolov and Illei, 2009). SS can be seen alone (primary SS, pSS) or in association with other autoimmune rheumatic diseases (secondary SS) (Vitali et al, 2002). We have focused on pSS in an effort to understand the etiology of salivary gland (SG) hypofunction in this autoimmune disease

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Conclusion