Deciphering the Dandida Albicans Hsp90 Kinase Interactome

This project aims to inform new treatments for Candida albicans, the leading fungal pathogen of humans. Aside from the common nonlethal infections, several hundred people die in the UK every year of bloodstream and organ infections caused by this yeast. It threatens patients whose immune defenses are already weakened from cancer chemotherapy, HIV/AIDS, surgery or by extremely low birth weight. Once Candida has spread through the bloodstream, it is extremely difficult to treat because it quickly develops resistance to currently available drugs. The emergence of drug resistances is facilitated by the heat shock protein 90 (Hsp90), which stabilizes other proteins, thus contributing to their activation. Hsp90 collaborates with Cdc37. Together they target signal transmitting proteins, so called kinases. The Hsp90/Cdc37 complex and its target kinases play an important role in the normal physiology of all cells. Sometimes though, Hsp90 goes astray. For example when it stabilizes cancer proteins in humans and promotes drug resistance in yeast. Both examples suggest that reducing Hsp90 may help fight cancer and yeast infections. Indeed, drugs reducing Hsp90 function are currently tested as anti-cancer drugs. Unfortunately though, human and yeast Hsp90 are very similar. This means, it is very difficult to reduce only yeast Hsp90 but not human Hsp90 to cure a life-threatening yeast infection. Animal models showed that reducing yeast Hsp90 in combination with drugs treating the yeast infection itself caused severe side effects. We will address this problem by investigating the role of Hsp90/Cdc37 and their associated kinases in yeast to understand how they contribute to the yeast's ability to cause life-threatening infections. Specifically, we aim to further advance our understanding of those kinases that are unique to yeast and that depend on Hsp90 as future drug targets. Targeting yeast specific components with a drug should prevent or at least drastically reduce side effects in patients. We previously showed that reducing Hsp90 in yeast cells that also lack one kinase causes yeast cell death. This could be a promising approach for the development of new drugs and treatment strategies. Especially since Hsp90 reducing drugs are already in clinical trial as anti-cancer drugs. We furthermore demonstrated that some kinases regulate Hsp90 and Cdc37, while many others depend on the Hsp90/Cdc37 for stability and activation. Yet, knowledge of the Hsp90/Cdc37 kinase signaling module is sparse in C. albicans. This project will examine the kinases that regulate the Hsp90/Cdc37 complex and the kinases that depend on Hsp90/Cdc37 by conducting three sets of experiments. First, we will determine how specific kinases regulate Hsp90 and Cdc37 and which parts of Hsp90/Cdc37 are indeed necessary for yeasts to cause disease. Second, we will focus on yeast specific kinases and study their role in yeast infections to understand, which is the most important kinase that would make the best drug target. Third, we will search the yeast genome for more kinases that depend on Hsp90 to widen the field of potential drug targets. Scientists and patients will benefit from our research. In the short-term, biologists will be able to translate our knowledge of the Hsp90/Cdc37 kinase circuitry to the disease-causing mechanisms they study in other fungi or microbes. Structural biologists could crystallize promising kinases to elucidate their structure, which is a prerequisite for drug development by pharmacologists. Since Hsp90 plays an important role in a number of biological processes, our results could be used by scientists investigating genetics, cancer biology, and microbiology. The long-term beneficiaries of our research will be patients in the UK and world-wide that suffer from yeast infections as our research could potentially lead to the development of new drugs to conquer life-threatening yeast infections.