Autophagy is a conserved cellular recycling pathway that is critical for cell homeostasis. In healthy cells, autophagy occurs constitutively at low basal levels and contributes to the routine turnover of cytosolic components and organelles within lysosomes. However, autophagy is also a stress response and can be induced by a change of environmental conditions such as starvation, oxidative stress, and invading pathogens. A growing body of evidence suggests that dysregulation of autophagy is critical for human diseases such as cancer, neurodegenerative disorders, heart and muscular diseases. In most settings autophagy acts as a cytoprotective, pro-survival pathway maintaining cellular/organismal viability during stresses, removing damaged organelles and toxic aggregates. We use biochemical approaches relying on quantitative mass spectrometry (MS)-based proteomics to study molecular mechanisms involved in autophagy, its influence on the cellular microenvironment and its role in skin disorders.
Kinases involved in autophagy regulation
Phosphorylation-based signaling is vital for the regulation of autophagy. Several kinase complexes were identified that are crucial for the negative or positive regulation of autophagy. In several projects, we study phosphorylation-based signaling in autophagy with the aim of (1) identifying new kinase complexes involved in autophagy regulation, and (2) characterizing new effectors of kinases known to be involved in autophagy. We employ chemoproteomics approaches and in vitro kinase assays coupled to MS-based readouts.
The role of ubiquitin in autophagy regulation and cargo selection
Ubiquitin, mainly known through its function in proteasomal degradation, is an important type of protein post-translational modification (PTM) that also plays a critical role in autophagy regulation and autophagosomal cargo selection. Historically, protein degradation performed by the ubiquitin-proteasome-system and autophagosomal/lysosomal degradation have been regarded as distinct, parallel degradation pathways. However lately, numerous interactions between these pathways and common molecular players were found. Polyubiquitinated protein aggregates are recognized by autophagy receptors that harbor an ubiquitin-binding domain and an autophagosomal targeting domain. These receptors are critical for autophagosomal/lysosomal degradation of polyubiquitinated substrates. We use MS-based approaches to generate a comprehensive overview and classification of ubiquitination events in autophagy.
Autophagy in skin
We could show that autophagy is dysregulated in skin fragility as well as in wound healing in a cell type dependent manner. Keratinocytes and skin fibroblast respond distinctly to genetic and environmental perturbations. We aim at a better understanding of the underlying molecular mechanisms and the role of the microenvironment on cell homeostasis.
Regulation of selectivity in mitophagy
Mitophagy, the autophagosomal targeting of mitochondria to lysosomes for degradation, is an important autophagy subtype that appears to be non-functional in neurodegenerative diseases. We study the role of mitophagy in selective degradation of mitochondrial matrix proteins.