Oxidative Stress-Induced STIM2 Cysteine Modifications Suppress Store-Operated Calcium Entry.

Christine Silvia Gibhardt, Sabrina Cappello, Rajesh Bhardwaj, Romana Schober, Sonja Agnes Kirsch, Zuriñe Bonilla Del Rio, Stefan Gahbauer, Anna Bochicchio, Magdalena Sumanska, Christian Ickes, Ioana Stejerean-Todoran, Miso Mitkovski, Dalia Alansary, Xin Zhang, Aram Revazian, Marc Fahrner, Victoria Lunz, Irene Frischauf, Ting Luo, Daria Ezerina, Joris Messens, Vsevolod Vadimovich Belousov, Markus Hoth, Rainer Arnold Böckmann, Matthias Albrecht Hediger, Rainer Schindl, Ivan Bogeski

Journal: Cell reports 2021;33(3):108292

PMID: 33086068

Free Full Text on Bern Open Repository and Information System View on PubMed

Abstract

Store-operated calcium entry (SOCE) through STIM-gated ORAI channels governs vital cellular functions. In this context, SOCE controls cellular redox signaling and is itself regulated by redox modifications. However, the molecular mechanisms underlying this calcium-redox interplay and the functional outcomes are not fully understood. Here, we examine the role of STIM2 in SOCE redox regulation. Redox proteomics identify cysteine 313 as the main redox sensor of STIM2 in vitro and in vivo. Oxidative stress suppresses SOCE and calcium currents in cells overexpressing STIM2 and ORAI1, an effect that is abolished by mutation of cysteine 313. FLIM and FRET microscopy, together with MD simulations, indicate that oxidative modifications of cysteine 313 alter STIM2 activation dynamics and thereby hinder STIM2-mediated gating of ORAI1. In summary, this study establishes STIM2-controlled redox regulation of SOCE as a mechanism that affects several calcium-regulated physiological processes, as well as stress-induced pathologies.

Address: Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany.; Department of Nephrology and Hypertension, Inselspital, University of Bern, Bern, Switzerland.; Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, Linz, Austria; Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria.; Computational Biology, Department of Biology, Friedrich-Alexander University of Erlangen-Nürnberg, Germany.; Light Microscopy Facility, Max Planck Institute of Experimental Medicine, Göttingen, Germany.; Biophysics, Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany.; Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, Linz, Austria.; VIB-VUB Center for Structural Biology, Brussels Center for Redox Biology, Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium.; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany; Pirogov Russian National Research Medical University, Moscow, Russia; Federal Center of Brain Research and Neurotechnologies of the Federal Medical Biological Agency, Moscow, Russia.; Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria. Electronic address: [email protected].; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany. Electronic address: [email protected].

DOI: 10.1016/j.celrep.2020.108292

Link outs

Free resources

Full Text Sources:

MeSH Terms: Calcium, Calcium Channels, Calcium Signaling, Cell Line, Tumor, Cysteine, Humans, Intracellular Calcium-Sensing Proteins, Neoplasm Proteins, ORAI1 Protein, Oxidation-Reduction, Oxidative Stress, Stromal Interaction Molecule 1, Stromal Interaction Molecule 2