Systematic analysis of post-translational regulation of autophagy protease ATG4B

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Autophagy can be regarded as a cellular self-cleaning process through which damaged and potentially toxic components are removed through degradation. This process is involved in the clearance of protein aggregates (as for example in neurodegenerative disorders), damaged organelles (induced by cellular stresses or extracellular toxins) or pathogens (such as bacteria or viruses). In addition, autophagy counteracts the deleterious effects associated with ageing as it helps clear the accumulation of toxic protein products and damaged material that accumulates over time. Accordingly, it is of high importance that this process is tightly controlled. Dysregulation of autophagy is commonly associated with severe diseases that can lead to cancer, Parkinson's disease or Alzheimer's disease, just to name a few. Autophagy can be induced through multiple mechanisms, including starvation, hypoxia, DNA damage or pathogen infection resulting in the formation of a double-membrane structure, the autophagosome. The autophagosome can remove defective organelles or complexes from cells and in most cases rescues the cell from potential harmful effects of the initial stressor. To understand these complex physiological conditions, it is of high importance to identify the molecular components involved and understand their interactions and regulation. The autophagy machinery has been well characterized both in human cells and in yeast. There is one main question remaining in the field: that is to characterize the molecular mechanisms by which these proteins interact. Further, there is a huge interest in drug discovery to utilize this knowledge to develop therapeutic strategies for diseases associated with autophagy. Here, we aim to identify the molecular regulation of one of the key enzymes involved in autophagy, ATG4B. In order to identify the regulation of this protein, we will make use of recent technical advances in genomics and proteomics and use a combination of high-throughput screening technologies and proteomic profiling. There will be a huge benefit in identifying specific molecular targets within the autophagy pathway as this will enable more focused drug discovery efforts. This project will shed light onto the signaling cascades that control an early step in autophagy and will provide to a general understanding of autophagy that will lead to the identification of potential novel therapeutic targets.