The Role of Plakophilin 1 in Inflammatory Signaling
Final Report Abstract
Plakophilin 1 (PKP1) provides stable desmosomal cohesion and regulates mRNA metabolism, translation as well as proliferation. Loss of function mutations of PKP1 cause the rare ectodermal dysplasia skin fragility syndrome (EDSFS) characterized by skin erosions accompanied by erythema, chronic perioral inflammation and recurrent skin infections. So far, an impaired physical barrier has been regarded as the primary cause of inflammation in EDSFS. Using WT compared to PKP1-depleted keratinocytes, we demonstrate a direct function of PKP1 in inhibiting inflammatory responses. PKP1 sequesters the DExD/H helicases DDX1, DDX3X, DDX21 and DHX15 to attenuate / control dsRNA-dependent innate immunity through an MDA5-MAVS-dependent signaling axis. The loss of PKP1 results in over-activation of IRF3 and NFκB leading to the increased expression of their respective target genes INF-β1, IL-6 and TNFα. Moreover, PKP1 is rapidly degraded via the proteasome after dsRNA stimulation, suggesting that the release of PKP1-bound DExD/H helicases is mandatory to induce a proper inflammatory response, and that their re-association might help to resolve or balance the inflammatory response, respectively. Taken together this shows, that PKP1 regulates tissue homeostasis by controlling dsRNA- induced innate immunity and contributes by securing the physical skin barrier to the pathogenesis of EDSFS and other inflammatory skin diseases.
Publications
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The armadillo protein p0071 controls KIF3 motor transport. Journal of Cell Science, 130(19), 3374-3387.
Becher, Alexander; Eiseler, Tim; Porzner, Marc; Walther, Paul; Keil, René; Bobrovich, Susanne; Hatzfeld, Mechthild & Seufferlein, Thomas
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14-3-3 proteins regulate desmosomal adhesion via plakophilins. Journal of Cell Science, 131(10).
Rietscher, Katrin; Keil, René; Jordan, Annemarie & Hatzfeld, Mechthild
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Plakophilin 1 but not plakophilin 3 regulates desmoglein clustering. Cellular and Molecular Life Sciences, 76(17), 3465-3476.
Fuchs, Michael; Foresti, Marco; Radeva, Mariya Y.; Kugelmann, Daniela; Keil, Rene; Hatzfeld, Mechthild; Spindler, Volker; Waschke, Jens & Vielmuth, Franziska
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Plakophilin 3 phosphorylation by ribosomal S6 kinases supports desmosome assembly. Journal of Cell Science, 133(8).
Müller, Lisa; Rietscher, Katrin; Keil, René; Neuholz, Marvin & Hatzfeld, Mechthild
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Desmosomes as Signaling Hubs in the Regulation of Cell Behavior. Frontiers in Cell and Developmental Biology, 9.
Müller, Lisa; Hatzfeld, Mechthild & Keil, René
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Plakophilin 3 facilitates G1/S phase transition and enhances proliferation by capturing RB protein in the cytoplasm and promoting EGFR signaling. Cell Reports, 42(1), 112031.
Müller, Lisa; Keil, René & Hatzfeld, Mechthild
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Plakophilin 4 controls the spatio-temporal activity of RhoA at adherens junctions to promote cortical actin ring formation and tissue tension. Cellular and Molecular Life Sciences, 81(1).
Müller, Lisa; Keil, René; Glaß, Markus & Hatzfeld, Mechthild
