Zinc-related IZH1 as a novel regulator of endoplasmic reticulum homeostasis in yeast

Endoplasmic reticulum (ER) homeostasis is maintained through tightly regulated processes that coordinate lipid metabolism and proteostasis. The ER-resident acyl-CoA diphosphatase FIT2, and its yeast homologue Scs3, are key regulators of this balance; their loss disrupts ER morphology and induces chronic ER stress, though the underlying mechanisms remain unclear. To uncover factors involved in Scs3-dependent ER maintenance, we conducted a genome-wide multicopy suppressor screen in <i>SCS3</i> knockout yeast cells, which display inositol auxotrophy. This analysis identified <i>IZH1</i>, a zinc-related ER membrane protein homologous to the human PAQR (Progestin and AdipoQ Receptor) family, as a genetic interactor of <i>SCS3</i>. <i>IZH1</i> overexpression enhanced <i>INO1</i> expression, partially restored the growth of <i>SCS3</i> knockout cells in inositol-deprived conditions, and reduced ER stress levels without correcting ER morphology defects. Moreover, <i>IZH1</i> overexpression attenuated unfolded protein response signaling during acute proteotoxic stress and normalized ER-associated degradation kinetics. Together, these findings identify Izh1 as a novel regulator of ER homeostasis and provide new insight into how FIT2/Scs3 influences ER function.