Orai1 inhibitor STIM2? regulates myogenesis by controlling SOCE dependent transcriptional factors.

ABSTRACT: Store-operated Ca²⁺ entry (SOCE), the fundamental Ca²⁺ signaling mechanism in myogenesis, is mediated by stromal interaction molecule (STIM), which senses the depletion of endoplasmic reticulum Ca²⁺ stores and induces Ca²⁺ influx by activating Orai channels in the plasma membrane. Recently, STIM2?, an eight-residue-inserted splice variant of STIM2, was found to act as an inhibitor of SOCE. Although a previous study demonstrated an increase in STIM2? splicing during in vitro differentiation of skeletal muscle, the underlying mechanism and detailed function of STIM2? in myogenesis remain unclear. In this study, we investigated the function of STIM2? in myogenesis using the C2C12 cell line with RNA interference-mediated knockdown and CRISPR-Cas-mediated knockout approaches. Deletion of STIM2? delayed myogenic differentiation through the MEF2C and NFAT4 pathway in C2C12 cells. Further, loss of STIM2? increased cell proliferation by altering Ca²⁺ homeostasis and inhibited cell cycle arrest mediated by the cyclin D1-CDK4 degradation pathway. Thus, this study identified a previously unknown function of STIM2? in myogenesis and improves the understanding of how cells effectively regulate the development process via alternative splicing.

SUBMITTER: Kim KM 

PROVIDER: S-EPMC6658661 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature