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

• Sjögren's syndrome is an autoimmune disease characterized by dysfunction and inflammation of the salivary and lacrimal glands
• The pathogenesis of Sjögren's syndrome has not been elucidated, but the role of viruses has been suggested.
• Ebv-miR-BART13-3p downregulates STIM1 affecting the calcium influx mechanisms that regulate salivary gland function.In this study we report that the EBV-specific microRNA ebv-miR-BART13-3p, that is significantly elevated in salivary glands of primary Sjögren's syndrome patients, targets stromal interacting molecule 1 (STIM1), a primary regulator of the store-operated Ca2 + entry pathway that is essential for salivary gland function. This interaction affects the intracellular Ca2 + entry and subsequently the Ca2 +-dependent activation of NFAT. Ebv-miR-BART13-3p is present in both B cells and salivary epithelial cells, even though EBV infects B cells and not salivary epithelial cells.We demonstrate here that ebv-miR-BART13-3p can be transferred from B cells to salivary epithelial cells through exosomes, recapitulating the functional effects on calcium signaling.

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.