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J Cell Sci. 2017 Oct 1;130(19):3222-3233. doi: 10.1242/jcs.201715. Epub 2017 Aug 9.

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

Author information

1
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
2
The Rockefeller University, New York, NY 10065, USA.
3
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Ospedale San Raffaele, Via Olgettina 58, 20132, Milan, Italy.
4
Institute of Biochemistry and Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue Str. 15, 60438 Frankfurt, Germany.
5
Center for Applied Medical Research, Department of Gene Therapy and Regulation of Gene Expression. University of Navarra, 55 Pio XII St. 31008 Pamplona, Spain.
6
Department of Biochemistry & Biophysics, University of California San Francisco and Howard Hughes Medical Institute, San Francisco, CA 94143, USA.
7
Center for Molecular Signaling, Institute of Medical Biochemistry and Molecular Biology, Saarland University, 66421 Homburg, Germany.
8
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Ospedale San Raffaele, Via Olgettina 58, 20132, Milan, Italy vananken.eelco@hsr.it maya.schuldiner@weizmann.ac.il.
9
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel vananken.eelco@hsr.it maya.schuldiner@weizmann.ac.il.

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 hits were 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 heme-dependent 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

PMID:
28794014
PMCID:
PMC5665437
DOI:
10.1242/jcs.201715
[Indexed for MEDLINE]
Free PMC Article

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