The keratin-desmosome scaffold as a signaling module during epithelial differentiation and wound healing
Final Report Abstract
In this project, we used mice and keratinocytes which lack the entire keratin cytoskeleton following deletion of keratin gene clusters, in comparison to normal controls, as model systems to investigate distinct keratin functions during epidermal differentiation. To investigate the function of individual keratins, keratin-deficient keratinocytes were reconstituted with select keratin isotypes. The comparison of keratin-deficient and normal control animals revealed a hitherto major role of keratins as constituents of the epidermal barrier. Proteomic and bioinformatics analysis revealed that keratins were essential for late, not early steps of cornified envelope/barrier formation. Biochemical and ultrastructural analysis revealed a keratin requirement in vivo for the correct composition and maintenance of functional desmosomes. The known consequences of a defective skin barrier prompted an investigation of inflammatory cytokines in keratin-deficient mouse skin, resulting in the discovery of elevated itch-inducing TSLP (thymic stromal lymphopoietin) levels in the skin of keratin-deficient mice. Analysis of keratin-deficient keratinocytes resulted in the discovery of a novel, keratin-dependent and keratinocyte-intrinsic mechanism triggering the upregulation of TSLP. Our current data suggest an upregulation of the EGFR ligand AREG that stimulation EGFR phosphorylation and TSLP activation via Erk1/2 in the absence of keratins. Given that we identified elevated TSLP levels in a group of EBS patients that correlated with the EBS score, our findings may be of relevance to the understanding of itch in EBS. Together with the finding that severe EBS-associated keratin mutations, such as K14R125P, compromise desmosome adhesion and desmoplakin localization at the plasma membrane, our data underscore that the pathophysiology of EBS is much more complex than previously appreciated. This insight may lead to the identification of new treatable disease targets.
Publications
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A keratin scaffold regulates epidermal barrier formation, mitochondrial lipid composition and activity. J Cell Biol 211, 1057-1075 (2015)
V Kumar, J-E Bouameur, J Bär, RH Rice, H-T Hornig-Do, DR Roop, N Schwarz, S Brodesser, S Thiering, RE Leube, RJ Wiesner, CB Brazel, S Heller, H Binder, H Wirth, P Seibel, and TM Magin
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Distinct impact of two keratin mutations causing EBS on cell-cell adhesion and keratinocyte stiffness. J Invest Dermatol, 135:2437-2445
M Homberg, L Ramms, N Schwarz, G Dreissen, RE Leube, R Merkel, B Hoffmann, TM Magin
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Keratin isotypes control desmosome stability and dynamics through PKCα. J Invest Dermatol, Oct 12
F Loschke, M Homberg, TM Magin
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Regulation of keratin network organization. Curr Op Cell Biol, Jan 13;32C:56-64
F Loschke, K Seltmann, J-E Bouameur and TM Magin
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Cross talk between the cytoplasm and nucleus during development and disease. Curr Opin Genet Dev. Apr 22;37:129-136
LL Wallrath, J Bohnekamp and TM Magin
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Keratin-dependent TSLP expression suggests a link between skin blistering and atopic disease. J Allergy Clin Immunol 2016 Nov;138(5):1461-1464.e6
V Kumar, M Behr, D Kiritsi, A Scheffschick, A Grahnert, M Homberg, A Schwieger-Briel, L Bruckner-Tuderman and TM Magin
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Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics. Cold Spring Harb Perspect Biol. 2017 Jun 1;9(6)
Hatzfeld M, Keil R, Magin TM
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A novel function for keratins in regulating the adhesive properties of desmosomal cadherins. J Invest Dermatol. 2018 Jan;138(1):121-131
F Vielmuth, M Radeva, M Hiermaier, MT Wanuske, F Loschke, TM Magin, J Waschke, V Spindler
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Keratin defects trigger the itch-inducing cytokine thymic stromal lymphopoietin via Areg-Egfr signalling. J Allergy Clin Immunol. December 2019, Volume 144, Issue 6, Pages 1719–1722
A Scheffschick, D Kiritsi and TM Magin
