Autophagy-Lysosome Pathways

mTORC1, Ulk1 and Vps34/Beclin 1 complexes

Three dynamic and interactive kinase complexes have been implicated in autophagy initiation: mTORC1 which, in the presence of nutrients and energy, inhibits autophagy; and the Ulk1 and Vps34/Beclin 1 complexes that promote autophagosome formation and maturation. To obtain a more comprehensive picture of the dynamic function of these complexes, we will analyze their composition, thereby linking autophagy signaling to the control of apoptosis, senescence, cell proliferation, metabolism and transformation.

Autophagy-Lysosome Pathways

Cellular networks controlling autophagic flux and lysosomal membrane integrity
Our genetic and proteomic screens have identified numerous proteins as essential regulators of autophagy and lysosomal membrane stability. We will employ bioinformatics tools, in particular molecular dynamics simulations, to reveal signaling pathways controlling the autophagy-lysosome network and to understand their interplay with each other and with other cellular processes. We will validate and characterize how the selected pathways regulate autophagy and lysosomes at the molecular level, and we will test their crosstalk with other cellular networks, focusing on those that regulate therapy-induced cell death, the stability of (auto)lysosomes, cell proliferation and the DNA damage response.

Modulation of autophagy in vivo

To understand the consequences of autophagy manipulation for the entire organism, we will use genetic and pharmacological manipulation of mice as the main model system. We will test our hypotheses first in 3D and organoid cultures, and in C. elegans, when appropriate.