Keratins are the most abundant proteins in epithelial cells, in which they occur as a cytoplasmic network of 10-12 nm wide intermediate filaments (IFs). They are encoded by an evolutionarily conserved multigene family, with > 49 individual members subdivided into two major types. The pairwise regulation of type I and type II keratin genes reflects a heteropolymerization requirement shared by all keratin IFs. Most keratin genes are regulated in pairwise, epithelial tissue-type and differentiation-specific fashion, the functional basis of which remains ill understood. A major role fulfilled by keratin IFs is to act as a resilient yet pliable scaffold that endows epithelial cells with the ability to sustain mechanical and non-mechanical stresses. Inherited mutations affecting the coding sequence of keratins are responsible for a large number of epithelial fragility disorders. Additional functions, manifested in a sequence- and context-dependent fashion, have been identified in recent years. Here we seek to further our understanding of the properties and functions of type II keratins expressed in complex epithelial tissues, including K1, K5 and K6 isoforms, and test our model that differential keratin expression leads to distinct mechanical attributes for keratinocytes. First, we will test the ability of K1 to rescue the striking epithelial defects that occur in K6 isoform null mice. We will concentrate on the epithelial fragility in the oral mucosa and the altered wound epithelialization phenotype seen in these mice. Second, we will investigate the biochemical and genetic bases for the strain-dependency of the enhanced migration exhibited by K6 isoform null keratinocytes in an ex vivo model of wound epithelialization. Third, we will assess the specific contribution of keratin IFs to the viscoelastic properties of live epithelial cells. Fourth, we will test the notion that the self-induced ability of keratin IFs to undergo bundle formation is required for their scaffolding function in vivo. In particular, we will focus on the contribution of nonhelical C-terminal tail domains to filament bundling and function. The proposed research will provide insight into keratin filament organization and function, the significance of differential keratin expression, and the mechanisms underlying blister formation in keratin-based blistering diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-OBM-2 (04))
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Moshell, Alan N
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Johns Hopkins University
Schools of Medicine
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Jacob, Justin T; Coulombe, Pierre A; Kwan, Raymond et al. (2018) Types I and II Keratin Intermediate Filaments. Cold Spring Harb Perspect Biol 10:
Coulombe, Pierre A (2017) The Molecular Revolution in Cutaneous Biology: Keratin Genes and their Associated Disease: Diversity, Opportunities, and Challenges. J Invest Dermatol 137:e67-e71
Coulombe, Pierre A (2016) Discovery of keratin function and role in genetic diseases: the year that 1991 was. Mol Biol Cell 27:2807-10
Wang, Fengrong; Zieman, Abigail; Coulombe, Pierre A (2016) Skin Keratins. Methods Enzymol 568:303-50
Feng, Xia; Coulombe, Pierre A (2015) Complementary roles of specific cysteines in keratin 14 toward the assembly, organization, and dynamics of intermediate filaments in skin keratinocytes. J Biol Chem 290:22507-19
Feng, Xia; Coulombe, Pierre A (2015) A role for disulfide bonding in keratin intermediate filament organization and dynamics in skin keratinocytes. J Cell Biol 209:59-72
van Steensel, Maurice A M; Coulombe, Pierre A; Kaspar, Roger L et al. (2014) Report of the 10th Annual International Pachyonychia Congenita Consortium Meeting. J Invest Dermatol 134:588-591
Alvarado, David M; Coulombe, Pierre A (2014) Directed expression of a chimeric type II keratin partially rescues keratin 5-null mice. J Biol Chem 289:19435-47
Chung, Byung-Min; Rotty, Jeremy D; Coulombe, Pierre A (2013) Networking galore: intermediate filaments and cell migration. Curr Opin Cell Biol 25:600-12
Pan, Xiaoou; Hobbs, Ryan P; Coulombe, Pierre A (2013) The expanding significance of keratin intermediate filaments in normal and diseased epithelia. Curr Opin Cell Biol 25:47-56

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