The Role of Plakophilin 1 in Inflammatory Signaling

• Applicant: Dr. René Keil
• Subject Area: Cell Biology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 404288583

The skin provides a life sustaining barrier to protect the host against various environmental insults. The skin mechanically limits water loss, prevents the entry of potentially damaging agents and is a constituent of the immune system. Disturbed barrier function contributes to the pathogenesis of skin diseases like psoriasis, atopic dermatitis and also cancer. The keratinocytes, the main cell type of the mammalian epidermis, facilitate barrier formation through their strong intercellular cohesion, provided by desmosomes. The loss of desmosomal cohesion as provoked by several autoimmune, genetic and microbial diseases that target desmosomal components are accompanied by chronic inflammations, disordered wound healing and multiple allergies. Although the contribution of the impaired barrier to these phenotypes is unquestionable, increasing evidence suggests a keratinocyte-intrinsic function of desmosomal proteins in regulating inflammatory responses. In this context the multifunctional plakophilin 1 (PKP1), which is essential for stable desmosomal cohesion and has also been described to regulate mRNA-metabolism, translation and proliferation, might play a central role. Loss-of-function mutations of PKP1 cause the rare but severe epidermal dysplasia skin fragility syndrome (EDSFS) characterized by skin erosions and accompanied by erythema, chronic perioral inflammation and recurrent skin infections.My preliminary data reveal an excessive inflammatory response in the skin of PKP1 knockout mice as well as in keratinocytes derived from these animals. PKP1 knockout keratinocytes secrete increased amounts of the primary response cytokines CXCL1 and IL-1α in the absence of exogenous inflammatory triggers. Upon poly I:C stimulation, used to mimic viral infections, the production of TNF-α, IL-6 as well as CXCL1 and IL-1α is strongly induced or further increased and exceeds the level of wildtype keratinocytes by a multiple. Elevated cytokine secretion correlates with elevated mRNA-levels and increased NFκB-activity, suggesting that PKP1 is required to dampen inflammatory responses by influencing inflammatory signaling pathways.In order to elucidate the molecular basis of this phenotype in PKP1 knockout mice and keratinocytes, and explain the multiple symptoms described for EDSFS, I want to decipher:(1) How does PKP1 regulate the transcription of primary response cytokines?(2) What are the consequences that arise from PKP1-dependent dysfunctional inflammatory responses? Taken together, this study will reveal the molecular basis for the role of PKP1 during inflammatory processes. Moreover, it will provide a profound basis for future investigations addressing the role of PKP1 in wound healing processes as well as inflammatory skin diseases and unravelling the pathways that modulate the versatile functions of PKP1.

• DFG Programme: Research Grants