FKBP8 and the autophagy-inducing Class-III PI3K Complex Roles of LIR dependent interactions

Abstract

Autophagy (Greek meaning “self eating”) is a renovation process in cells. Dysfunctional autophagy plays a major role in human diseases including cancer, inflammatory and neurodegenerative diseases. Misfolded or aggregated proteins, damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as intracellular pathogens are degraded by autophagy. During the process, the components that are going to be degraded are encapsulated by a double membrane structure called the autophagosome, which delivers its contents to the lysosome for degradation. Mitochondria is an important cellular organelle, providing energy to the cell by generating the energy molecule adenosine triphosphate through oxidative phosphorylation. This process generates reactive oxygen species that may lead to DNA damage and mutations, as byproducts. Therefore, a healthy population of mitochondria is critical for the well-being of cells. Mitophagy is the selective degradation of mitochondria by autophagy, mediated by specific proteins sitting on the mitochondria outer surface. These proteins cooperate with autophagosomal membrane proteins to deliver the damaged or surplus mitochondria to the lysosome. The PhD thesis work of Zambarlal Bhujabal carried out in the Molecular Cancer Research Group, under guidance of Professor Terje Johansen, focuses on the process of mitophagy and the formation of autophagosomes. This work identifies the outer mitochondrial protein FKBP8 as a mitophagy-mediating protein. FKBP8 was found to cooperate with the autophagosomal membrane protein to clear damaged mitochondria. Interestingly, FKBP8 was further identified to stimulate autophagy in general, probably mediated by interactions with specific proteins at different steps of the autophagy process. In addition, some of the important proteins involved in the formation the autophagosome forming a Phosphatidylinositol kinase complex required for generation of autophagosomes were studied. It was found that ATG14, Beclin-1 and VPS34 bound to the autophagosomal membrane protein GABARAP via short sequence motifs. Notably, during this work, FKBP8 was also found to interact with the Phosphatidylinositol kinase complex member, Beclin-1.