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

• Published in: Cell reports (Cambridge) 2020-10, Vol.33 (3), p.108292-108292, Article 108292
• Main Authors: Gibhardt, Christine Silvia, Cappello, Sabrina, Bhardwaj, Rajesh, Schober, Romana, Kirsch, Sonja Agnes, Bonilla del Rio, Zuriñe, Gahbauer, Stefan, Bochicchio, Anna, Sumanska, Magdalena, Ickes, Christian, Stejerean-Todoran, Ioana, Mitkovski, Miso, Alansary, Dalia, Zhang, Xin, Revazian, Aram, Fahrner, Marc, Lunz, Victoria, Frischauf, Irene, Luo, Ting, Ezerina, Daria, Messens, Joris, Belousov, Vsevolod Vadimovich, Hoth, Markus, Böckmann, Rainer Arnold, Hediger, Matthias Albrecht, Schindl, Rainer, Bogeski, Ivan
• Format: Article
• Language: English
• Subjects: calcium; Calcium - metabolism; Calcium Channels - metabolism; Calcium Signaling; Cell Line, Tumor; cysteine; Cysteine - metabolism; Humans; ICRAC; Intracellular Calcium-Sensing Proteins - metabolism; melanoma; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; ORAI; ORAI1 Protein - metabolism; Oxidation-Reduction; Oxidative Stress - physiology; redox; ROS; SOCE; STIM2; Stromal Interaction Molecule 1 - genetics; Stromal Interaction Molecule 1 - metabolism; Stromal Interaction Molecule 2 - genetics; Stromal Interaction Molecule 2 - metabolism; Stromal Interaction Molecule 2 - physiology; thiol
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108292

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. [Display omitted] •Compared with STIM1, STIM2 has 10 additional cytosolic cysteines•STIM2 oxidation inhibits store-operated Ca2+ entry•Redox proteomics identifies C313 as the redox sensor of STIM2•Oxidation of C313 prevents STIM2-STIM2 oligomerization The ER-residing STIM2 protein gates ORAI Ca2+ channels at the plasma membrane. However, the functional relevance of STIM2 is not fully understood. Gibhardt et al. reveal a regulatory mechanism in which oxidation of C313 controls STIM2 function. Oxidative stress-induced C313 sulfonylation hinders STIM2 oligomerization, causing inhibition of store-operated Ca2+ entry.