Originally identified in association with the B vitamins, inositol is an essential eukaryotic metabolite that is a component of a major class of membrane phospholipids, and also functions in signal transduction and in a variety of other capacities. Defects in the inositol system have been linked to a number of diseases such as diabetes and manic depression. Inositol is also present in plants, and is important in agriculture and in industrial processes. We are studying how the cellular demand for inositol is coordinated to its supply routes in the eukaryotic model system Saccharomyces cerevisiae.

Inositol supply mechanisms include transport of external inositol into the cell and biosynthesis of inositol by the cell. Each of these processes is highly regulated. Our recent work on transport of external inositol has revealed several superimposed layers of regulation, including genetic regulation of transcription and regulation at the level of protein stability. We showed that the Itr1 inositol permease has characteristics expected for a membrane transporter, but is regulated like a receptor by a process akin to receptor-mediated endocytosis (RME). The unusual form of Itr1 permease RME is triggered by inositol, is dependent on ubiquitin conjugation, and results in destabilization of the permease. We recently found that changes in protein stability also play a major role in control of transcription in this system.

We are also studying the distinct roles of internal inositol and external inositol in the different forms of regulation that govern inositol supply. Repression of transcription of the key genes depends primarily on external inositol, as does destabilization of Itr1 permease. Our preliminary evidence indicates that an efflux pump is a key component that responds to internal inositol. Our long-term goal is to understand how the cells "senses" both the internal and external availability of inositol, and how this information is relayed to the complex regulatory apparatus.