Metalloregulation of yeast membrane steroid receptor homologs

Zinc is an essential micronutrient that can also be toxic. An intricate mechanism exists in yeast that maintains cellular zinc within an optimal range. The centerpiece of this mechanism is the Zap1p protein, a transcription factor that senses zinc deficiency and responds by up-regulating genes involved in zinc metabolism. A microarray screen for novel Zap1p target genes suggested a role in zinc homeostasis for four homologous yeast genes. The expression of two of these genes, YDR492w and YOL002c, suggested direct regulation by Zap1p, whereas the expression of YOL002c and a third homologous gene, YOL101c, was induced by high zinc. YDR492w and YOL002c are confirmed to be direct Zap1p target genes. The induction of YOL002c and YOL101c by toxic metal ion exposure is shown to be mediated by the Mga2p hypoxia sensor. Furthermore, YOL101c is induced by deletion of the Aft1p iron-responsive transcription factor. These three genes, along with a fourth yeast homolog, YLR023c, have phenotypic effects on zinc tolerance and Zap1p activity. Because of their metalloregulation, zinc-related phenotypes, and highly conserved motifs containing potential metal-binding residues, this family has been renamed the IZH gene family (Implicated in Zinc Homeostasis). Furthermore, these genes are regulated by exogenous fatty acids, suggesting a dual role in lipid metabolism. The IZH genes encode membrane proteins that belong to a ubiquitous protein family that includes hemolysin III and vertebrate membrane steroid receptors. We propose that the IZH genes affect zinc homeostasis either directly or indirectly by altering sterol metabolism.