Autophagy Signaling Group
Head: Prof. Christian Behrends
Autophagy is a fundamental, evolutionarily conserved, cellular process that enables cells to engulf and digest portions of their cytoplasm in a regulated manner. Physiological roles of autophagy range from removal of damaged or surplus organelles and turnover of stable, long-lived proteins and other macromolecules, via supply of nutrients and energy for essential anabolic needs under conditions of nutrient deprivation or growth factor withdrawal, to clearance of potentially toxic aggregate-prone proteins and elimination of intracellular pathogens, including viruses, parasites and bacteria. Consequently, autophagy is intricately linked to a broad range of health and disease states including tissue homeostasis, organismal development and aging, suppression of tumour development, prevention of neurodegeneration, inflammation, innate and adaptive immunity. Aberrant regulation of autophagy has been associated with cancer, cardiomyopathy, Huntington’s, Parkinson’s and Crohn’s disease.
Fig. 1 Overview of autophagy, showing of autophagosome and autolysosome development (Top). Core mammalian autophagy machinery and autophagy receptors. PI3P, phosphatidylinositol 3-phosphate; PE, Phosphatidylethanolamine (Bottom).
Autophagy proceeds through two major steps: First, a double-lipid bilayer is nucleated that expands and wraps around cargo yielding a closed multi-lamellar organelle termed autophagosome. Second, autophagosomes fuse heterotypically with endosomes and lysosomes, thereby gradually acquiring lysosomal properties and maturing into an acidic, degradative hybrid organelle known as autolysosome. The molecular core machinery that orchestrates convoluted formation of autophagosomes encompasses the ULK1 serine/threonine kinase complex, the hVps34 class III phosphatidylinositol 3-kinase complex, phosphatidylinositol 3-phosphate (PI3P) binding proteins, an ubiquitin-like protein (Ubl) conjugation system with two different Ubls (ATG8 and ATG12) and the transmembrane protein ATG9 (Fig. 1). Autolysosome inception is generally thought to employ many components that are shared with other endocytic pathways in the cell such as transport from early-to-late endosomes and phagosome-to-phagolysosome maturation, which all funnel their substrates to lysosomes.
Although individual modules within the autophagy pathway are relatively well characterized, particularly in yeast, many questions remain. First, what are the major regulatory inputs into core signaling modules in the pathway, and how are these inputs linked with the cellular environment? Second, to what extent do distinct modules within the large autophagy system communicate with each other? Third, what molecular changes in the architecture of the autophagy network, including complex composition and post-translational modifications, occur upon induction of autophagy? Fourth, how is cargo selected for delivery to the lumen of the autophagosome and what controls the specificity of this process? We employ multiple biochemical (mutagenesis, binding and reconstitution studies), cell biological (flow cytometry, confocal and time-lapse microscopy-based assays) and pseudo-genetic (RNAi) techniques centered about mass spectrometry-based proteomics and image-based high-content screening platforms to address these open questions. Our research interests are paired with a strong collaborative network in Frankfurt: http://www.fan.uni-frankfurt.de/wiki/
The Autophagy Signaling Group is welcoming applications from motivated people with a keen interest in molecular and cellular aspects of autophagy (See positions).
Read the interview with Christian in the Journal of Cell Science JCS interview