Phosphoinositide-based switches in endocytic membrane traffic and signaling.
Phosphoinositides (PIPs) regulate nearly all aspects of cell physiology ranging from cell signaling to membrane
compartmentalization and organelle dynamics. A hallmark of PIP function is their rapid interconversion by PIP
kinases and phosphatases, which underlies PIP-based functional switches in endolysosomal membrane traffic
and in cell signaling. How PIP switches operate in space and time in most cases is incompletely understood.
In the past funding period, we have focused on the analysis of PIP-based functional switches that operate
during endocytosis and endosomal recycling and within the endolysosomal system. A key result from the
current funding period has been the discovery of an endosomal phosphatidylinositol 3-phosphate [PI(3)P]-
based mechanism that controls mitochondrial function via reshaping of the endoplasmic reticulum. A further
milestone has been the revelation of a novel pathway for the nutrient-dependent control of lysosome function
and lysosome-based nutrient signaling that is based on a local PI(3)P/ phosphatidylinositol 4-phosphate
[PI(4)P] switch module. Lipid switch-dependent rewiring of organellar membrane dynamics thus appears to
represent a fundamental concept to adapt cells to fluctuating nutrient environments. In further studies, we have
unraveled antagonistic roles of the endosomal PI(3)P phosphatase MTM1 and the class II PI 3-kinase PI3KC2
in the recycling and endocytosis of active integrins to the cell surface of muscle cells. Additional work has
revealed a function of endosomal PI(3)P in the control of neurotransmission via its effects on the exo-endocytic
cycling of synaptic vesicle membranes and on the roles of distinct isoforms of class II PI3-kinases in mTORC1
signaling in the brain and in the last step of cytokinesis.
In the next funding period, we will capitalize on these findings and novel tools generated by the
Johnsson lab and MF [Schultz] to address how the endolysosomal proteome and lipidome are altered in
response to nutrients or stressors and to identify the pathways that control lipid content, morphology and
function of endolysosomes, e.g. membrane contact sites. Ultimately, we aim for a comprehensive
understanding of the role of PIP switches in endolysosomal function that may be of relevance for our
understanding of dysregulated PIP homeostasis diseases.
Prof. Dr. Volker Haucke (FMP Berlin)
PD. Dr. Carsten Schultz (EMBL Heidelberg), until 09/2019