Role of keratins in inflammation and epidermal barrier function
The epidermal barrier protects the body against dehydration, inflammation and mechanical injury. It is formed predominantly from keratinocytes. For a long time, the respective contribution of keratinocytes and immune cells to chronic inflammatory skin disorders like atopic dermatitis and psoriasis has been unclear. Increasing evidence supports a primary role of keratinocytes in initiating such disorders. Using knockout mice for keratin K1, we have recently shown that this keratin is involved in regulating secretion of the pro-inflammatory cytokine IL-18 from keratinocytes, suggesting that certain keratin mutations may predispose to barrier disorders in humans. We are currently investigating this in several mouse and cell culture models.
Analysis of the keratin-desmosome scaffold
Epithelia are highly cohesive tissues, based on desmosomes, in addition to adherens junctions. How desmosomes are regulated during differentiation, wound healing and metastasis, is largely unknown. We have recently identified a novel, PKCalpha and keratin-dependent mechanism which regulates desmoplakin localization at the plasma membrane and its endocytosis. Currently, we address a number of questions: how is keratin-desmosome interaction regulated by growth factors? To which extent is adhesive strength of desmosomes dependent on their contact with keratins? How is the keratin-desmosome scaffold regulated during tumour formation and metastasis? What is the role of posttranslational modifications in regulating keratin interactions and organization?
Keratins as determinants of cell mechanics, migration and invasion
The micromechanical properties of tissues, in particular of epithelia, are largely determined by the cytoskeleton and its interaction with the extracellular matrix. While actin has long been regarded as a major contributor of cell stiffness, the role of keratin intermediate filament proteins has been neglected. During collaborations with Profs. Käs (Leipzig) and Merkel (Jülich) we have recently demonstrated a major role of keratins as determinants of cell stiffness. In the absence of keratins, keratinocytes are much softer and more invasive, supporting the view that downregulation of keratins, as observed during epithelial mesenchymal transition, promotes invasive cell behaviour. Among the questions to be addressed are: what is the role of posttranslational keratin modifications in modulating cell stiffness and invasiveness? What are the key signaling pathways that regulate this? How do keratins contribute to cell migration?
Pathomechanisms of keratinopathies
Missense mutations in epidermal keratin genes cause a large number of dominant, blistering and in some cases, life-threatening disorders, including epidermolysis bullosa simplex and epidermolytic hyperkeratosis. The molecular mechanisms underlying these disorders are complex and are characterized by the collapse of the keratin cytoskeleton into cytoplasmic aggregates. In addition to cell/tissue fragility, mutant keratins compromise cell matrix and intercellular adhesion, trigger itch by upregulation of the cytokine TSLP and affect overall keratinocyte differentiation. Currently, no causal therapies for EBS are available. Based on our previous finding that overexpression of the cochaperone CHIP reduces keratin aggregation, we hypothesize that drugs that promote formation of proper keratin cytoskeleton in the presence of mutant keratins should improve skin resilience and the overall quality of life of EBS patients.
To that end, we are currently screening libraries of chemical compounds that enable formation of a stress-resilient keratin cytoskeleton. This project is performed by Dr. Katrin Rietscher in collaboration with Dr. Jonny Sexton (University of Michigan, Ann Arbor) and Prof M. Bishr Omary (Rutgers University). It is funded by DEBRA Austria.