The response of the endoplasmic reticulum (ER) to stress and its need to adjust protein homeostasis is regulated by the unfolded protein response (UPR). The ER-membrane protein Ire1 is central to activation of the UPR as it senses accumulation of unfolded proteins or a change in the composition of the ER membrane. Ire1 thereby clusters into foci upon stress to enable optimal UPR activation. On page 3222, Maya Schuldiner, Eelco van Anken and colleagues used this ability of Ire1 to form clusters as a read-out in a screen for mutant yeast genes that are involved in stress signalling. Among the genes identified, they found many effectors of iron and iron-dependent haem homeostasis. The authors confirmed that iron levels affect the dynamics of Ire1 clustering and activation of the UPR in both human and yeast cells, and that the availability of iron is a limiting factor for the response of Ire1 to ER stress. They suggest that this is through haem availability. Several enzymes of the ergosterol biosynthesis pathway depend on haem, and the loss of sterols in the membrane affected Ire1 clustering and the ability of cells to survive ER stress. Furthermore, the authors suggest that a feedback loop exists between ergosterol synthesis, levels of iron and the ER stress response. This work establishes the requirement of iron and haem for membrane architecture through haem-dependent sterol biosynthesis to exert an efficient UPR response for stress signalling in eukaryotic cells.
