One of the major focuses of the laboratory is focusing on understanding the regulation of enzymes that modify lipid phosphoinositides.
Lipid phosphoinositides are lipid second messengers that play fundamental roles in almost all aspects of a cells life and death. One of the most important lipid phosphoinositides is phosphatidylinositol 4 phosphate (PI4P). This lipid plays key roles in mediating cytokinesis and membrane traffic, and it is also the biosynthetic precursor for the signaling phosphoinositides phosphatidylinositol (4,5) bisphosphate (PIP2) and phosphatidylinositol (3,4,5) trisphosphate (PIP3). PI4P is generated through the action of the phosphatidylinositol 4-kinase (PI4K) family of enzymes.
We have a particular interest in understanding the molecular basis of regulation of two specific families of phosphoinositide kinases, the phosphatidylinositol 4 kinases (PI4Ks) and the phosphoinositide 3 kinases (PI3Ks).
PI4Ks are known to play essential roles in many cellular and pathogenic processes, but the molecular mechanism of how these enzymes are regulated is unclear. Interestingly these enzymes have been shown to mediate their cellular roles through both catalytic and non-catalytic functions. Many of these functions are dependent on interactions with protein binding partners. Determining the molecular basis of these interactions will be essential to understanding PI4Ks cellular functions. As these enzymes carry out their catalysis on lipid surfaces another major determinant of their activation is through their proper recruitment, assembly and activation on membrane surfaces. This has made studying the molecular basis of their regulation extremely challenging. PI4Ks are of intense clinical interest, as many pathogenic RNA viruses, including Poliovirus, Hepatitis C Virus, and Rhinovirus, require PI4K as an obligate host factor to generate PI4P enriched membranes necessary for intracellular viral replication. Also inhibitors that target PI4K in the causative parasite of malaria have been shown to be potent anti-malarial agents. Defining the molecular basis of how PI4Ks are regulated will be essential to develop novel therapeutic strategies for diseases mediated by PI4K signaling.