Studies on Fortilin-Prohibitin Interaction

Abstract: Apoptosis, programmed cell death, is a tightly regulated process that occurs in development, in tissue maintenance and turnover, and in regulating the immune system. Alterations in apoptosis regulation is known to be involved in various diseases including cancer, autoimmune diseases, and cardiovascular diseases including atherosclerosis initiation and maintenance. Fortilin is an antiapoptotic protein with a wide tissue distribution and a wide range of functions. fortilin has no sequence homology to other regulators of apoptosis, such as the Bcl-2 Proteins or the Inhibitors of Apoptosis proteins. In elucidating the mechanism of Fortilin-mediated cellular protection, fortilin protein interactions have been previously shown to modulate the cellular response to apoptotic stimuli. The goal of this dissertation is to investigate novel fortilin protein interactions in order to further shed light on the mechanism of fortilin mediated protection. In a proteomic screen fortilin was shown to interact with the anti-proliferative protein, prohibitin. I demonstrate that fortilin specifically interacts with this protein through in vitro studies. fortilin co-localizes with prohibitin in a perinuclear distribution and subcellular studies showed that fortilin and prohibitin are found in the nucleus, cytosol, and to a lesser degree in the endoplasmic reticulum. Fortilin was shown to mutually stabilize prohibitin. Finally, cells overexpressing fortilin and prohibitin attenuate the apoptosis response of cells compared to cells overexpressing either protein alone. In summary, these findings demonstrate a novel protein interaction between fortilin and prohibitin and shows a functional significance in modulating apoptosis after inducing cell stress.