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

Nir Cohen,Michal Breker,Anush Bakunts,Kristina Pesek,Ainara Chas,J. Argemí,A. Orsi,Lihi Gal,S. Chuartzman,Yoav Wigelman,Felix Jonas,P. Walter,R. Ernst,T. Aragón,E. van Anken,M. Schuldiner

Published 2017 in Journal of Cell Science

ABSTRACT

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. Highlighted Article: To respond to folding stress in the ER, cells activate the conserved sensor Ire1. We show that iron is required for optimal Ire1 activation and suggest this is because iron is required for ergosterol biosynthesis.

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