Iron affects Ire1 clustering propensity and the amplitude of endoplasmic reticulum stress signaling

Nir Cohen; Michal Breker; Anush Bakunts; Kristina Pesek; Ainara Chas; Josepmaria Argemí; Andrea Orsi; Lihi Gal; Silvia Chuartzman; Yoav Wigelman; Felix Jonas; Peter Walter; Robert Ernst; Tomás Aragón; Eelco van Anken; Maya Schuldiner

doi:10.1242/jcs.201715

Iron affects Ire1 clustering propensity and the amplitude of endoplasmic reticulum stress signaling

Nir Cohen, Michal Breker, Anush Bakunts, Kristina Pesek, Ainara Chas, Josepmaria Argemí, Andrea Orsi, Lihi Gal, Silvia Chuartzman, Yoav Wigelman, Felix Jonas, Peter Walter, Robert Ernst, Tomás Aragón, Eelco van Anken^*, Maya Schuldiner

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

The unfolded protein response (UPR) allows cells to adjust secretory pathway capacity according to need. Ire1, the endoplasmic reticulum (ER) stress sensor and central activator of the UPR is conserved from the budding yeast Saccharomyces cerevisiae to humans. Under ER stress conditions, Ire1 clusters into foci that enable optimal UPR activation. To discover factors that affect Ire1 clustering, we performed a high-content screen using a whole-genome yeast mutant library expressing Ire1-mCherry. We imaged the strains following UPR induction and found 154 strains that displayed alterations in Ire1 clustering. The hitswere enriched for iron and heme effectors and binding proteins. By performing pharmacological depletion and repletion, we confirmed that iron (Fe³⁺) affects UPR activation in both yeast and human cells. We suggest that Ire1 clustering propensity depends on membrane composition, which is governed by hemedependent biosynthesis of sterols. Our findings highlight the diverse cellular functions that feed into the UPR and emphasize the cross-talk between organelles required to concertedly maintain homeostasis.

Original language	American English
Pages (from-to)	3222-3233
Number of pages	12
Journal	Journal of Cell Science
Volume	130
Issue number	19
DOIs	https://doi.org/10.1242/jcs.201715
State	Published - 2017
Externally published	Yes

Bibliographical note

Funding Information:
This work was performed through support of the Deutsche Forschungsgemeinschaft (DFG SFB1190 grant Compartmental Gates and Contact Sites to M.S.) and a Volkswagen Foundation (grant 93091 to M.S. and R.E.). M.B. was supported by a Junior Fellow award from the Simons Foundation. M.S. is an Incumbent of the Dr. Gilbert Omenn and Martha Darling Professorial Chair in Molecular Genetics. E.v.A acknowledges financial support by the Giovanni Armenise-Harvard Foundation, Associazione Italiana per la Ricerca sul Cancro (MFAG13584) and Ministero della Salute (RF-2011-02352852). T.A. acknowledges financial support from the Ministerio de Economıáy Competitividad (grants SAF2010-19239 and BFU2013-48703-P), a Ramon y Cajal contract from the Spanish Ministerio de Ciencia e Innovación, and from the I3 program of the Ministerio de Economıáy Competitividad. P.W. is an investigator of the Howard Hughes Medical Institute. Deposited in PMC for immediate release.

Publisher Copyright:
© 2017.

Keywords

Heme
Ire1
Iron
Saccharomyces cerevisiae
Sterol
UPR

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10.1242/jcs.201715

Cite this

Cohen, N., Breker, M., Bakunts, A., Pesek, K., Chas, A., Argemí, J., Orsi, A., Gal, L., Chuartzman, S., Wigelman, Y., Jonas, F., Walter, P., Ernst, R., Aragón, T., van Anken, E., & Schuldiner, M. (2017). Iron affects Ire1 clustering propensity and the amplitude of endoplasmic reticulum stress signaling. Journal of Cell Science, 130(19), 3222-3233. https://doi.org/10.1242/jcs.201715

@article{99e0debf501a40f1a32afdae5bdcec1f,

title = "Iron affects Ire1 clustering propensity and the amplitude of endoplasmic reticulum stress signaling",

abstract = "The unfolded protein response (UPR) allows cells to adjust secretory pathway capacity according to need. Ire1, the endoplasmic reticulum (ER) stress sensor and central activator of the UPR is conserved from the budding yeast Saccharomyces cerevisiae to humans. Under ER stress conditions, Ire1 clusters into foci that enable optimal UPR activation. To discover factors that affect Ire1 clustering, we performed a high-content screen using a whole-genome yeast mutant library expressing Ire1-mCherry. We imaged the strains following UPR induction and found 154 strains that displayed alterations in Ire1 clustering. The hitswere enriched for iron and heme effectors and binding proteins. By performing pharmacological depletion and repletion, we confirmed that iron (Fe3+) affects UPR activation in both yeast and human cells. We suggest that Ire1 clustering propensity depends on membrane composition, which is governed by hemedependent biosynthesis of sterols. Our findings highlight the diverse cellular functions that feed into the UPR and emphasize the cross-talk between organelles required to concertedly maintain homeostasis.",

keywords = "Heme, Ire1, Iron, Saccharomyces cerevisiae, Sterol, UPR",

author = "Nir Cohen and Michal Breker and Anush Bakunts and Kristina Pesek and Ainara Chas and Josepmaria Argem{\'i} and Andrea Orsi and Lihi Gal and Silvia Chuartzman and Yoav Wigelman and Felix Jonas and Peter Walter and Robert Ernst and Tom{\'a}s Arag{\'o}n and {van Anken}, Eelco and Maya Schuldiner",

note = "Funding Information: This work was performed through support of the Deutsche Forschungsgemeinschaft (DFG SFB1190 grant Compartmental Gates and Contact Sites to M.S.) and a Volkswagen Foundation (grant 93091 to M.S. and R.E.). M.B. was supported by a Junior Fellow award from the Simons Foundation. M.S. is an Incumbent of the Dr. Gilbert Omenn and Martha Darling Professorial Chair in Molecular Genetics. E.v.A acknowledges financial support by the Giovanni Armenise-Harvard Foundation, Associazione Italiana per la Ricerca sul Cancro (MFAG13584) and Ministero della Salute (RF-2011-02352852). T.A. acknowledges financial support from the Ministerio de Economı{\'a}y Competitividad (grants SAF2010-19239 and BFU2013-48703-P), a Ramon y Cajal contract from the Spanish Ministerio de Ciencia e Innovaci{\'o}n, and from the I3 program of the Ministerio de Economı{\'a}y Competitividad. P.W. is an investigator of the Howard Hughes Medical Institute. Deposited in PMC for immediate release. Publisher Copyright: {\textcopyright} 2017.",

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doi = "10.1242/jcs.201715",

language = "American English",

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Cohen, N, Breker, M, Bakunts, A, Pesek, K, Chas, A, Argemí, J, Orsi, A, Gal, L, Chuartzman, S, Wigelman, Y, Jonas, F, Walter, P, Ernst, R, Aragón, T, van Anken, E & Schuldiner, M 2017, 'Iron affects Ire1 clustering propensity and the amplitude of endoplasmic reticulum stress signaling', Journal of Cell Science, vol. 130, no. 19, pp. 3222-3233. https://doi.org/10.1242/jcs.201715

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T1 - Iron affects Ire1 clustering propensity and the amplitude of endoplasmic reticulum stress signaling

AU - Cohen, Nir

AU - Breker, Michal

AU - Bakunts, Anush

AU - Pesek, Kristina

AU - Chas, Ainara

AU - Argemí, Josepmaria

AU - Orsi, Andrea

AU - Gal, Lihi

AU - Chuartzman, Silvia

AU - Wigelman, Yoav

AU - Jonas, Felix

AU - Walter, Peter

AU - Ernst, Robert

AU - Aragón, Tomás

AU - van Anken, Eelco

AU - Schuldiner, Maya

N1 - Funding Information: This work was performed through support of the Deutsche Forschungsgemeinschaft (DFG SFB1190 grant Compartmental Gates and Contact Sites to M.S.) and a Volkswagen Foundation (grant 93091 to M.S. and R.E.). M.B. was supported by a Junior Fellow award from the Simons Foundation. M.S. is an Incumbent of the Dr. Gilbert Omenn and Martha Darling Professorial Chair in Molecular Genetics. E.v.A acknowledges financial support by the Giovanni Armenise-Harvard Foundation, Associazione Italiana per la Ricerca sul Cancro (MFAG13584) and Ministero della Salute (RF-2011-02352852). T.A. acknowledges financial support from the Ministerio de Economıáy Competitividad (grants SAF2010-19239 and BFU2013-48703-P), a Ramon y Cajal contract from the Spanish Ministerio de Ciencia e Innovación, and from the I3 program of the Ministerio de Economıáy Competitividad. P.W. is an investigator of the Howard Hughes Medical Institute. Deposited in PMC for immediate release. Publisher Copyright: © 2017.

PY - 2017

Y1 - 2017

N2 - The unfolded protein response (UPR) allows cells to adjust secretory pathway capacity according to need. Ire1, the endoplasmic reticulum (ER) stress sensor and central activator of the UPR is conserved from the budding yeast Saccharomyces cerevisiae to humans. Under ER stress conditions, Ire1 clusters into foci that enable optimal UPR activation. To discover factors that affect Ire1 clustering, we performed a high-content screen using a whole-genome yeast mutant library expressing Ire1-mCherry. We imaged the strains following UPR induction and found 154 strains that displayed alterations in Ire1 clustering. The hitswere enriched for iron and heme effectors and binding proteins. By performing pharmacological depletion and repletion, we confirmed that iron (Fe3+) affects UPR activation in both yeast and human cells. We suggest that Ire1 clustering propensity depends on membrane composition, which is governed by hemedependent biosynthesis of sterols. Our findings highlight the diverse cellular functions that feed into the UPR and emphasize the cross-talk between organelles required to concertedly maintain homeostasis.

AB - The unfolded protein response (UPR) allows cells to adjust secretory pathway capacity according to need. Ire1, the endoplasmic reticulum (ER) stress sensor and central activator of the UPR is conserved from the budding yeast Saccharomyces cerevisiae to humans. Under ER stress conditions, Ire1 clusters into foci that enable optimal UPR activation. To discover factors that affect Ire1 clustering, we performed a high-content screen using a whole-genome yeast mutant library expressing Ire1-mCherry. We imaged the strains following UPR induction and found 154 strains that displayed alterations in Ire1 clustering. The hitswere enriched for iron and heme effectors and binding proteins. By performing pharmacological depletion and repletion, we confirmed that iron (Fe3+) affects UPR activation in both yeast and human cells. We suggest that Ire1 clustering propensity depends on membrane composition, which is governed by hemedependent biosynthesis of sterols. Our findings highlight the diverse cellular functions that feed into the UPR and emphasize the cross-talk between organelles required to concertedly maintain homeostasis.

KW - Heme

KW - Ire1

KW - Iron

KW - Saccharomyces cerevisiae

KW - Sterol

KW - UPR

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DO - 10.1242/jcs.201715

M3 - Article

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AN - SCOPUS:85030540440

SN - 0021-9533

VL - 130

SP - 3222

EP - 3233

JO - Journal of Cell Science

JF - Journal of Cell Science

IS - 19

ER -

Iron affects Ire1 clustering propensity and the amplitude of endoplasmic reticulum stress signaling

Abstract

Bibliographical note

Keywords

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