Research Project 1:
A role for human WIPI3 in lysosomal phosphoinositide signaling
Project Summary
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). Our previous 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. As mTORC1 knowingly inhibits autophagy, WIPI3 is likely involved in overriding mTORC1, thereby allowing autophagy initiation. In this project we engage to decipher the role of WIPI3 as a potential PI(3,5)P2 effector of TSC-dependent lysosomal signaling and mTORC1 regulation. Our project will shed light on the function of WIPI3 in lysosomal phosphoinositide signaling in normal and pathological circumstances.
References
Proikas-Cezanne T, Takacs Z, Dönnes P, Kohlbacher O (2015). “WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome.” Journal of Cell Science 128(2):207-17
Bakula D, Müller AJ, Zuleger T, Takacs Z, Franz-Wachtel M, Thost AK, Brigger D, Tschan MP, Frickey T, Robenek H, Macek B, Proikas-Cezanne T (2017). “WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy.” Nature Communications 8:15637
Bakula D, Mueller AJ, Proikas-Cezanne T (2017). “WIPI β-propellers function as scaffolds for STK11/LKB1-AMPK and AMPK-related kinase signaling in autophagy.” Autophagy 4: 1-2