Cell Reports (Oct 2020)
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
Affiliations
- Christine Silvia Gibhardt
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany
- Sabrina Cappello
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany
- Rajesh Bhardwaj
- Department of Nephrology and Hypertension, Inselspital, University of Bern, Bern, Switzerland
- Romana Schober
- Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, Linz, Austria; Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
- Sonja Agnes Kirsch
- Computational Biology, Department of Biology, Friedrich-Alexander University of Erlangen-Nürnberg, Germany
- Zuriñe Bonilla del Rio
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany
- Stefan Gahbauer
- Computational Biology, Department of Biology, Friedrich-Alexander University of Erlangen-Nürnberg, Germany
- Anna Bochicchio
- Computational Biology, Department of Biology, Friedrich-Alexander University of Erlangen-Nürnberg, Germany
- Magdalena Sumanska
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany
- Christian Ickes
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany
- Ioana Stejerean-Todoran
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany
- Miso Mitkovski
- Light Microscopy Facility, Max Planck Institute of Experimental Medicine, Göttingen, Germany
- Dalia Alansary
- Biophysics, Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany
- Xin Zhang
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany
- Aram Revazian
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany
- Marc Fahrner
- Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, Linz, Austria
- Victoria Lunz
- Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, Linz, Austria
- Irene Frischauf
- Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, Linz, Austria
- Ting Luo
- VIB-VUB Center for Structural Biology, Brussels Center for Redox Biology, Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium
- Daria Ezerina
- VIB-VUB Center for Structural Biology, Brussels Center for Redox Biology, Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium
- Joris Messens
- VIB-VUB Center for Structural Biology, Brussels Center for Redox Biology, Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium
- Vsevolod Vadimovich Belousov
- 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
- Markus Hoth
- Biophysics, Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany
- Rainer Arnold Böckmann
- Computational Biology, Department of Biology, Friedrich-Alexander University of Erlangen-Nürnberg, Germany
- Matthias Albrecht Hediger
- Department of Nephrology and Hypertension, Inselspital, University of Bern, Bern, Switzerland
- Rainer Schindl
- Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria; Corresponding author
- Ivan Bogeski
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University, Göttingen, Germany; Corresponding author
- Journal volume & issue
-
Vol. 33,
no. 3
p. 108292
Abstract
Summary: 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.
