The task of the S100 Fused-Type Protein Hornerin in skin defense

• Applicants: Professor Dr. Andreas Tholey; Professor Dr. Stephan Weidinger, since 4/2017
• Subject Area: Dermatology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 347702995

Different microbial species occupy skin surface habitats. To control the microbial growth at this interface, human skin possesses several protective barriers, including the well-known antimicrobial peptides. Despite the high microbial load, healthy human skin usually shows no signs of infection or inflammation. In agreement, many classical antimicrobial peptides (AMPs) are not activated or induced. The physical barrier of the skin, namely the stratum corneum, is obviously able to control microbes at this interface.Indeed, in stratum corneum extracts we identifed many peptide-fragments of known epidermal structural proteins that exhibit antimicrobial activity but only at more skin relevant acidic conditions, and especially against Pseudomonas aeruginosa.The vast majority of those fragments belong to the S100 Fused-Type protein Hornerin. In contrast to most known classical AMPs we were able to show that the antimicrobial activity of the Hornerin-fragments is not based on the amino acid sequence but rather on the composition, its size and N- and C-termini. Moreover, the antimicrobial spectrum is fragment-specific, and can be altered also by posttranslational modifications. Contrary to what was assumed and described for most of the amphipathic AMPs, our investigations reveal that the antimicrobial action of Hornerin-fragments is not due to direct membrane pore formation. Instead the peptide fragments were located within the cytoplasm of treated microbes there interacting with ribosomes, thus killing the bacteria by a yet unknown mechanism.We assume that different antimicrobially active Hornerin-fragments are generated in dependence of a given proteolytic activity of endogenous and/or even exogenous (microbial) proteases. When these fragments are taken up by certain microbes, intracellular disturbances of molecular mechanisms activate a stress-induced bacterial cell-death.We therefore like to investigate, which host and/or bacterial derived proteolytic mechanisms generate Hornerin-fragments, are differences exist in the fragmentation pattern at certain human skin locations, and how posttranslational modifications are involved in this antimicrobial defense. Further aims of this proposal are to enlighten the bacterial uptake and translocation of Hornerin-fragments to the cytoplasm, and to identify intracellular targets that perhaps causing a stress-induced cell death.In addition to basic-research-oriented results in the field of human epidermal defense, our insights will contribute to the development of new antimicrobials and strategies to treat infections.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Ulrich Gerstel, until 3/2017