The ER stress sensor IRE1 interacts with STIM1 to promote store-operated calcium entry, T cell activation, and muscular differentiation
Amado Carreras-Sureda,
Xin Zhang,
Loann Laubry,
Jessica Brunetti,
Stéphane Koenig,
Xiaoxia Wang,
Cyril Castelbou,
Claudio Hetz,
Yong Liu,
Maud Frieden,
Nicolas Demaurex
Affiliations
Amado Carreras-Sureda
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland; Corresponding author
Xin Zhang
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
Loann Laubry
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
Jessica Brunetti
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
Stéphane Koenig
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
Xiaoxia Wang
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Cyril Castelbou
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
Claudio Hetz
Biomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile, Santiago, Chile; FONDAP Center for Geroscience (GERO), Brain Health and Metabolism, Santiago, Chile; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
Yong Liu
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan 430072, China
Maud Frieden
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
Nicolas Demaurex
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
Summary: Store-operated Ca2+ entry (SOCE) mediated by stromal interacting molecule (STIM)-gated ORAI channels at endoplasmic reticulum (ER) and plasma membrane (PM) contact sites maintains adequate levels of Ca2+ within the ER lumen during Ca2+ signaling. Disruption of ER Ca2+ homeostasis activates the unfolded protein response (UPR) to restore proteostasis. Here, we report that the UPR transducer inositol-requiring enzyme 1 (IRE1) interacts with STIM1, promotes ER-PM contact sites, and enhances SOCE. IRE1 deficiency reduces T cell activation and human myoblast differentiation. In turn, STIM1 deficiency reduces IRE1 signaling after store depletion. Using a CaMPARI2-based Ca2+ genome-wide screen, we identify CAMKG2 and slc105a as SOCE enhancers during ER stress. Our findings unveil a direct crosstalk between SOCE and UPR via IRE1, acting as key regulator of ER Ca2+ and proteostasis in T cells and muscles. Under ER stress, this IRE1-STIM1 axis boosts SOCE to preserve immune cell functions, a pathway that could be targeted for cancer immunotherapy.
