DFG FOR 2625

Mechanisms of Lysosomal Homeostasis: "A role for human WIPI3 in lysosomal phosphoinositide signaling"

01/10/2017 to 30/09/2020

Lysosomal function and associated lysosomal degradation pathways, such as autophagy, depend on PI(3,5)P2 and PI3P signaling. Imbalanced levels of PI(3,5)P2 and PI3P, e.g. due to mutation in FIG4, a phosphoinositide 5-phosphatase, in Charcot-Marie-Tooth neuropathy type 4J (CMT4J), lead to flawed lysosomal function and obstructed autophagy. The underlying molecular mechanism is poorly understood. We anticipate that the roles of PI3P and PI(3,5)P2 regarding normal or disease-associated lysosome functions will be clarified by understanding the functions of PI3P- and PI(3,5)P2-binding proteins, namely the WIPI (WD-repeat protein interacting with phosphoinositide) proteins, which we previously identified (WIPI1-4). WIPI1 and WIPI2 bind predominantly to PI3P and function as PI3P effectors at the nascent autophagosome. In addition, our preliminary work revealed that WIPI3 predominantly binds to PI(3,5)P2, and that it associates with Tuberous Sclerosis complex (TSC complex) proteins on lysosomes. We hypothesize that WIPI3 functions as a PI(3,5)P2 effector on lysosomes, thereby being critical in TSC-mediated mTORC1 inhibition. Our project will shed light on the function of WIPI3 in lysosomal phosphoinositide signaling in normal and pathological circumstances.