Modulation of intracellular calcium signaling by microRNA-34a-5p

Caroline Diener,Hans-Peter Lenhof,Barbara A Niemeyer,Tobias Fehlmann,Eckart Meese,Vanessa Poth,Friedrich Grässer,Andreas Keller,Stefanie Rheinheimer,Martin Hart,Jennifer Menegatti,Barbara Walch-Rückheim,Dalia Alansary

doi:10.1038/s41419-018-1050-7

Caroline Diener, Hans-Peter Lenhof + Show 11 more

Open Access

https://doi.org/10.1038/s41419-018-1050-7

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Journal: Cell Death & Disease	Publication Date: Sep 27, 2018
Citations: 26	License type: open-access

Affiliation: Saarland University

Abstract

Adjusting intracellular calcium signaling is an important feature in the regulation of immune cell function and survival. Here we show that miR-34a-5p, a small non-coding RNA that is deregulated in many common diseases, is a regulator of store-operated Ca2+ entry (SOCE) and calcineurin signaling. Upon miR-34a-5p overexpression, we observed both a decreased depletion of ER calcium content and a decreased Ca2+ influx through Ca2+ release-activated Ca2+ channels. Based on an in silico target prediction we identified multiple miR-34a-5p target genes within both pathways that are implicated in the balance between T-cell activation and apoptosis including ITPR2, CAMLG, STIM1, ORAI3, RCAN1, PPP3R1, and NFATC4. Functional analysis revealed a decrease in Ca2+ activated calcineurin pathway activity measured by a reduced IL-2 secretion due to miR-34a-5p overexpression. Impacting SOCE and/or downstream calcineurin/NFAT signaling by miR-34a-5p offers a possible future approach to manipulate immune cells for clinical interventions.

Highlights

Store-operated Ca2+ entry (SOCE) is the central calcium signaling pathway in T cells, regulating cellular activation, proliferation, and migration[1]
We recently showed that miR-34a targets several members of the protein kinase C family, which functions in Ca2+ signaling through T-cell receptor (TCR)
We show that miR-34a-5p is a key regulator of SOCE and calcineurin signaling

Summary

Introduction

Store-operated Ca2+ entry (SOCE) is the central calcium signaling pathway in T cells, regulating cellular activation, proliferation, and migration[1]. Upon T-cell receptor (TCR) activation, the second messenger IP3 (inositol 1,4,5-trisphosphate) binds to its receptor in the membrane of endoplasmic reticulum (ER) resulting in a depletion of ER Ca2+ stores[5,6,7]. This in turn causes conformational changes and oligomerization of the ER Ca2+ sensor STIM (stromal interaction molecule), accompanied by translocation to the plasma membrane[8,9,10].

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