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Abstract
In the yeast Saccharomyces cerevisiae, the CKI1-encoded choline kinase catalyzes the committed step in the synthesis of phosphatidylcholine via the CDP-choline branch of the Kennedy pathway. Analysis of a P(CKI1)-lacZ reporter gene revealed that CKI1 expression was regulated by intracellular levels of the essential mineral zinc. Zinc depletion resulted in a concentration-dependent induction of CKI1 expression. This regulation was mediated by the zinc-sensing and zinc-inducible transcriptional activator Zap1p. A purified Zap1p probe interacted with two putative UAS(ZRE) sequences (ZRE1 and ZRE2) in the CKI1 promoter. Mutations of ZRE1 and ZRE2 to a nonconsensus UAS(ZRE) attenuated the induction of CKI1 expression in response to zinc depletion. A UAS(INO) element in the CKI1 promoter was responsible for stimulating CKI1 expression, but this element was not involved with the regulation by zinc depletion. The induction of CKI1 expression in zinc-depleted cells translated into increased choline kinase activity in vitro and in vivo, and an increase in phosphatidylcholine synthesis via the Kennedy pathway.
Highlights
The zinc transporters are regulated at the level of gene expression, and the most highly regulated transporter is
Whereas little is known about the role of phospholipids in the structure and/or function of zinc transporters, it is known that the synthesis of membrane phospholipids in S. cerevisiae is coordinately regulated with the expression of zinc transporters in response to zinc depletion [1]
The synthesis of phospholipids is coordinately regulated with the expression of zinc transporters that control zinc homeostasis in S. cerevisiae [1]
Summary
Pathway) by interaction with Ino2p, a component of the transcriptional activator Ino2p-Ino4p complex that interacts with a UASINO in the promoter [1, 36]. Because of the complementary nature of the phospholipid synthesis pathways in S. cerevisiae, we hypothesized that the decrease in CDP-DAG pathway enzyme activities is compensated by an increase in PC synthesis via the CDP-choline branch of the Kennedy pathway (Fig. 1). Choline kinase is a highly regulated enzyme that is controlled by transcriptional [41,42,43] and post-translational [44, 45] mechanisms to regulate PC content in S. cerevisiae. We found that the expression of CKI1 was induced by zinc depletion, and that the mechanism for this regulation involved the zinc-regulated transcriptional activator Zap1p. This transcriptional regulation translated into increased choline kinase activity and PC synthesis via the Kennedy pathway
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