Department Molecular Pharmacology and Cell Biology (Volker Haucke)

Research topics of the Haucke lab

The focus of research in the Haucke laboratory is the dissection of the molecular mechanisms of exo-endocytosis and endolyososomal membrane dynamics and its role in cell signaling, especially in the nervous system (Kononnenko & Haucke, Neuron 2015). The laboratory uses a wide range of technologies that include biochemical and molecular biological approaches in vitro, chemical biology and screening technology, super-resolution microscopy as well as genetic manipulations at the organismic level in vivo. The overarching goal of these studies is to provide a mechanistic understanding of exo-endocytosis and endolysosomal membrane dynamics and its regulation by proteins and lipids and to use this know-how to develop novel strategies for acute chemical and pharmacological interference.

Research within the Haucke lab can be grossly divided into two major themes:

(1) The role of exo-endocytic and endolysosomal proteins within the brain, especially in the maintenance of neurotransmission at chemical synapses, and

(2) The regulation of membrane homeostasis in endocytosis & in the endolysosomal system by phosphoinositides and phosphoinositide metabolizing enzymes.

Over the past decade the Haucke lab has made significant contributions in both of these areas.

Posor et al., Nature 2013

Using a combination of fluorescence-based imaging approaches including live cell confocal and total internal reflection (TIRF) microscopy together with in vivo systems we have gained a number of important and novel insights into the interplay between membrane-associated proteins and lipids in clathrin-dependent endocytosis, synaptic vesicle recycling, and endosomal membrane dynamics.

Our laboratory pioneered the study of adaptors that sort specific synaptic vesicle proteins in the brain. For example, we have identified and characterized AP180 and stonin 2 as sorting adaptors that are required for the maintenance of vesicular pools of the key essential synaptic vesicle proteins synaptobrevin and synaptotagmin (Koo et al., Neuron 2015; Kononenko et al., Proc. Natl. Acad. Sci. USA 2013; Diril et al., Dev. Cell 2006) and of protein complexes that aid sorting efficacy (Kaempf et al., Proc. Natl. Acad. Sci. USA 2015). We have also made the surprising observation that membrane retrieval at synapses occurs in part by clathrin-independent endocytosis, while clathrin and its major endocytic adaptor AP-2 regenerate synaptic vesicles from internal endosome-like vacuoles in addition to their action at the plasma membrane (Kononenko et al., Neuron 2014; Kononenko & Haucke, Neuron 2015). These studies are currently being pursued further by cutting-edge technology including optogenetics and flash-freeze electron microscopy approaches paired with genetics.

Recent research from our laboratory has unravelled a mechanism for phosphoinositide conversion at endosomes that enables exit from the endosomal system by local conversion of phosphatidylinositol 3-phosphate [PI(3)P] to phosphatidylinositol 4-phosphate [PI(4)P]. Our results further suggest that defective phosphoinositide conversion at endosomes underlies X-linked centronuclear myopathy caused by loss of the myotubularin phosphatase MTM1 in humans (Ketel et al., Nature 2016).

Moreover, we have identified phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) as a novel key lipid in endocytosis. Formation of PI(3,4)P2 by class II phosphatidylinositol-3-kinase C2α (PI(3)K C2α) spatiotemporally controls clathrin-mediated endocytosis (Posor et al., Nature 2013), suggesting a pathway for phosphoinositide conversion at the plasma membrane en route to endosomes (Daumke et al., Cell 2014). We currently explore other novel functions of this lipid in cell signaling and endolysosomal membrane traffic. Furthermore, we have unravelled important regulatory pathways that contribute to the synthesis of select pools of endosomal phosphatidylinositol 4-phosphate [PI(4)P] in Wnt signaling (Wieffer et al., Curr Biol., 2013; Mössinger et al., EMBO Rep., 2012) and have identified regulatory mechanisms that contribute to PI(4,5)P2 synthesis at synapses (Krauß et al., J. Cell Biol. 2003; Krauß et al., Proc. Natl. Acad. Sci. USA 2006; Krauß & Haucke, EMBO Rep. 2007). Moreover, the Haucke lab has developed the first known small molecule inhibitors of clathrin function (von Kleist et al., Cell 2011). These compounds, named pitstops selectively block endocytic ligand association with the clathrin terminal domain as confirmed by X-ray crystallography. Furthermore, we could show that pitstop-induced inhibition of clathrin function acutely interferes with receptor-mediated endocytosis, entry of HIV, and synaptic vesicle recycling caused by a dramatic increase in the lifetimes of clathrin coat components.

Leibniz-Institut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)