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

doi:10.1016/j.celrep.2020.108292

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 EzerinaJoris Messens, Vsevolod Vadimovich Belousov, Markus Hoth, Rainer Arnold Böckmann, Matthias Albrecht Hediger, Rainer Schindl, Ivan Bogeski

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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.

Originele taal-2	English
Artikelnummer	108292
Tijdschrift	Cell Reports
Volume	33
Nummer van het tijdschrift	3
DOI's	https://doi.org/10.1016/j.celrep.2020.108292
Status	Published - 20 okt 2020

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10.1016/j.celrep.2020.108292Licentie: CC BY

Oxidative Stress-Induced STIM2Final published version, 8,94 MBLicentie: CC BY

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Gibhardt, C. S., Cappello, S., Bhardwaj, R., Schober, R., Kirsch, S. A., Bonilla Del Rio, Z., Gahbauer, S., Bochicchio, A., Sumanska, M., Ickes, C., Stejerean-Todoran, I., Mitkovski, M., Alansary, D., Zhang, X., Revazian, A., Fahrner, M., Lunz, V., Frischauf, I., Luo, T., ... Bogeski, I. (2020). Oxidative Stress-Induced STIM2 Cysteine Modifications Suppress Store-Operated Calcium Entry. Cell Reports, 33(3), [108292]. https://doi.org/10.1016/j.celrep.2020.108292

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. / Oxidative Stress-Induced STIM2 Cysteine Modifications Suppress Store-Operated Calcium Entry. In: Cell Reports. 2020 ; Vol. 33, Nr. 3.

@article{93e637facf8248798da4e077a89fbc49,

title = "Oxidative Stress-Induced STIM2 Cysteine Modifications Suppress Store-Operated Calcium Entry",

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.",

author = "Gibhardt, {Christine Silvia} and Sabrina Cappello and Rajesh Bhardwaj and Romana Schober and Kirsch, {Sonja Agnes} and {Bonilla Del Rio}, Zuri{\~n}e and Stefan Gahbauer and Anna Bochicchio and Magdalena Sumanska and Christian Ickes and Ioana Stejerean-Todoran and Miso Mitkovski and Dalia Alansary and Xin Zhang and Aram Revazian and Marc Fahrner and Victoria Lunz and Irene Frischauf and Ting Luo and Daria Ezerina and Joris Messens and Belousov, {Vsevolod Vadimovich} and Markus Hoth and B{\"o}ckmann, {Rainer Arnold} and Hediger, {Matthias Albrecht} and Rainer Schindl and Ivan Bogeski",

year = "2020",

month = oct,

day = "20",

doi = "10.1016/j.celrep.2020.108292",

language = "English",

volume = "33",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "3",

}

Gibhardt, CS, Cappello, S, Bhardwaj, R, Schober, R, Kirsch, SA, Bonilla Del Rio, Z, Gahbauer, S, Bochicchio, A, Sumanska, M, Ickes, C, Stejerean-Todoran, I, Mitkovski, M, Alansary, D, Zhang, X, Revazian, A, Fahrner, M, Lunz, V, Frischauf, I, Luo, T, Ezerina, D , Messens, J, Belousov, VV, Hoth, M, Böckmann, RA, Hediger, MA, Schindl, R & Bogeski, I 2020, 'Oxidative Stress-Induced STIM2 Cysteine Modifications Suppress Store-Operated Calcium Entry', Cell Reports, vol. 33, nr. 3, 108292. https://doi.org/10.1016/j.celrep.2020.108292

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

In: Cell Reports, Vol. 33, Nr. 3, 108292, 20.10.2020.

Onderzoeksoutput: Article › peer review

TY - JOUR

T1 - Oxidative Stress-Induced STIM2 Cysteine Modifications Suppress Store-Operated Calcium Entry

AU - Gibhardt, Christine Silvia

AU - Cappello, Sabrina

AU - Bhardwaj, Rajesh

AU - Schober, Romana

AU - Kirsch, Sonja Agnes

AU - Bonilla Del Rio, Zuriñe

AU - Gahbauer, Stefan

AU - Bochicchio, Anna

AU - Sumanska, Magdalena

AU - Ickes, Christian

AU - Stejerean-Todoran, Ioana

AU - Mitkovski, Miso

AU - Alansary, Dalia

AU - Zhang, Xin

AU - Revazian, Aram

AU - Fahrner, Marc

AU - Lunz, Victoria

AU - Frischauf, Irene

AU - Luo, Ting

AU - Ezerina, Daria

AU - Messens, Joris

AU - Belousov, Vsevolod Vadimovich

AU - Hoth, Markus

AU - Böckmann, Rainer Arnold

AU - Hediger, Matthias Albrecht

AU - Schindl, Rainer

AU - Bogeski, Ivan

PY - 2020/10/20

Y1 - 2020/10/20

N2 - 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.

AB - 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.

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U2 - 10.1016/j.celrep.2020.108292

DO - 10.1016/j.celrep.2020.108292

M3 - Article

C2 - 33086068

VL - 33

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 3

M1 - 108292

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

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