Funcitonal analysis of keration-dependent melanosome and vesicle traffic in keratinocytes
Final Report Abstract
The epidermis protects an organism against mechanical injury, dehydration and regulates immune homeostasis by virtue of epidermal keratinocytes. Transfer of melanosomes from melanocytes through keratinocytes contributes to the protection of keratinocyte genetic material from sunlight. Melanosomes provide this protection by forming a supranuclear cap on top of keratinocyte nuclei. The mechanisms which contribute to the distribution of melanosomes, the protection against mechanical and other insults in keratinocytes are not well understood. Accumulating evidence suggests that many keratinocyte functions depend on structural proteins including keratins. Keratins constitute the intermediate filament cytoskeleton in all epithelia. In this project, we investigated whether keratins are involved in melanosome distribution and in additional functions maintaining skin homeostasis. To address these questions, we searched for keratin-interacting proteins and investigated novel functions for keratin K1, mutations in which can cause pigmentation defects in skin. To that end, we established K1 ko mice which turned out an unexpected and surprising phenotype. We found that in the mouse, this keratin is not essential to maintain skin integrity but controls an inflammatory network in murine keratinocytes. Absence of K1 caused a prenatal increase in interleukin-18 (IL-18) and S100A8/A9, accompanied by a barrier defect and perinatal lethality. We confirmed a major role of IL-18 as a driver in the pathology by genetic depletion of IL-18. This partially rescued K1ko mice. IL-18 release was keratinocyteautonomous, K1- and caspase-9-dependent, supporting an upstream role of K1 in the pathology. Finally, transcriptome profiling revealed a K1-mediated gene expression signature similar to atopic eczema and psoriasis, but different from Krt5-deficiency and epidermolysis bullosa simplex. Our data suggest a functional link between K1 and human inflammatory skin diseases. The finding that K1 is not crucial to maintain skin integrity but to control skin inflammation via IL-18, demonstrated by the genetic rescue of K1 ko by IL-18 ko mice was completely unexpected. The finding provides the basis for a novel concept on keratins in skin homeostasis.
Publications
- Identification of a keratin-associated protein with a putative role in vesicle transport. Eur. J. Cell Biol. 86, 827-839 (2007)
L Planko, C Böhse, J. Höhfeld, RC Betz, S Eigelshoven, S Hanneken, S Pasternack, H Büssow, K Van Den Bogaert, M Braun-Falco, A Rütten, MA. Rogers, T Ruzicka, MM Nöthen, R Kruse, TM Magin
- Structural and regulatory functions of keratins. Exp. Cell Res. 313, 2021-2032 (2007)
TM Magin, P Vijayaraj and RL Leube
- Cytokines as genetic modifiers in K5-/-mice and in human epidermolysis bullosa simplex. Human Mutation 30, 832-841 (2009)
W Roth, U Reuter, C Wohlenberg, L Bruckner-Tuderman and TM Magin
- Targeting of mutant keratins by CHIP offers a novel therapy approach for the dominant skin disorder epidermolysis bullosa simplex. Human Mutation 31, 466-476 (2010)
S Löffek, S Wöll, J Höhfeld, RE Leube, C Has, L Bruckner-Tuderman and TM Magin
- Cytoskeleton in Motion: The Case of Keratin Intermediate Filaments. J Cell Biol. 194, 669-678 (2011)
R Windoffer, M. Beil, TM Magin and RL Leube
- Keratin function and regulation in tissue homeostasis and pathogenesis. BioMolec Concepts 3, 161-173 (2012)
W Roth, M Hatzfeld, M Friedrich, S Thiering and TM Magin
- Targeting the palm: a leap forward towards treatment of keratin disorders. J Invest Dermatol. 132, 1541-1542 (2012)
W Roth, M Hatzfeld and TM Magin
- Verrucous carcinoma in epidermolysis bullosa simplex is possibly associated with a novel mutation in the keratin 5 gene. Br J Dermatol, Vol. 167. 2012, Issue 4, pp. 929-936.
H. Schumann, W. Roth ,C. Has, A. Volz, C. Erfurt-Berge, T.M. Magin, L. Bruckner-Tuderman
(See online at https://doi.org/10.1111/j.1365-2133.2012.11075.x)
