Keratins are the most abundant proteins in surface epithelia, in which they form cytoplasmic networks of 10 nm wide intermediate filaments (IFs). Keratins are encoded by an evolutionarily conserved multigene family, with 54 individual members subdivided into two major types (I and II). The pairwise regulation of type I and type II keratins in epithelia reflects a strict heteropolymerization requirement. In addition, keratin gene are regulated in an epithelial tissue-type and differentiation-specific fashion, the functional bass of which is only partly understood. Our efforts in this project are focused on defining the properties and function of the type I keratins 16 and 17 (K16, K17), and type II keratins 6a and 6b (K6a, K6b) in skin epithelia, which are of particular interest because of their dual involvement in human disease. First, genetic mutations in Krt6a/b, Krt16 or Krt17 cause genodermatoses with pathological features reflecting grossly altered skin homeostasis, including pachyonychia congenita (PC), palmoplantar keratoderma (PPK), and steatocystoma multiplex. The main tissues affected by these disorders are ectoderm-derived epithelial appendages and glabrous skin, and represent the sites of constitutive expression of these genes. Second, elevated expression of these keratin genes impacts the onset and course of chronic hyperproliferative and inflammatory skin diseases, e.g., psoriasis and cancer. The latter results from the massive induction of these keratin proteins in interfollicular epidermis under such abnormal circumstances, combined with their emerging role as regulators of cell growth, tissue inflammation and immune responses in skin epithelia. During the last period of support, we discovered that a nuclear form of K17 plays a significant role in regulating the expression of genes involved in growth control, inflammation and immunity in skin keratinocytes. Going forward, we propose to:
(Aim 1 a) Identify the mechanisms and regulation of import/export of K17 to/from the nucleus, and identify the protein partners of K17 inside the nucleus;
(Aim 1 b) Map K17 protein binding sites throughout the genome of resting versus stimulated skin keratinocytes;
and (Aim 1 c) Generate and characterize a mouse in which K17 cannot be imported in the nucleus but is otherwise fully functional. We also showed that the PPK lesions that spontaneously arise in Krt16 null mice resemble those occurring in PC patients and are in part the result of hypoactive Keap1-Nrf2 signaling. Going forward we will:
(Aim 2 a) Assess the consequence of expressing PC-causing missense Krt16 alleles in mouse;
(Aim 2 b) Define the mechanism(s) through which K16 regulates Keap1/Nrf2-dependent gene expression;
and (Aim 2 c) Identify other protein partners and pathways through which K16 regulates innate immunity and the skin barrier. Upon completion of this project we hope to have defined the significance of the presence of keratin 17 in the nucleus, thus paving the way for efforts to assess the general importance of this property among keratins, and to have established that activating Nrf2 function presents a genuine opportunity for the therapy of PC/PPK.
Keratins are the major cytoskeletal proteins in epithelial cells, in which they provide key structural support and protection against various forms of stress. Genetic defects in keratin proteins account for a large number of epithelial disorders, the pathophysiology of which is only partially understood and for which there currently are no effective treatment options. Efforts in this project are focused on discovering novel roles of keratin proteins that are relevant to skin diseases and may inspire the development of therapies.
| Jacob, Justin T; Coulombe, Pierre A; Kwan, Raymond et al. (2018) Types I and II Keratin Intermediate Filaments. Cold Spring Harb Perspect Biol 10: |
| Wang, Fengrong; Chen, Song; Liu, Hans B et al. (2018) Keratin 6 regulates collective keratinocyte migration by altering cell-cell and cell-matrix adhesion. J Cell Biol 217:4314-4330 |
| Zieman, Abigail; Coulombe, Pierre A (2018) The keratin 16 null phenotype is modestly impacted by genetic strain background in mice. Exp Dermatol 27:672-674 |
| Kerns, Michelle L; Hakim, Jill M C; Zieman, Abigail et al. (2018) Sexual Dimorphism in Response to an NRF2 Inducer in a Model for Pachyonychia Congenita. J Invest Dermatol 138:1094-1100 |
| 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 |
| Hobbs, Ryan P; Jacob, Justin T; Coulombe, Pierre A (2016) Keratins Are Going Nuclear. Dev Cell 38:227-33 |
| Hobbs, R P; Batazzi, A S; Han, M C et al. (2016) Loss of Keratin 17 induces tissue-specific cytokine polarization and cellular differentiation in HPV16-driven cervical tumorigenesis in vivo. Oncogene 35:5653-5662 |
| Kerns, Michelle L; Hakim, Jill M C; Lu, Rosemary G et al. (2016) Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes. J Clin Invest 126:2356-66 |
| Wang, Fengrong; Zieman, Abigail; Coulombe, Pierre A (2016) Skin Keratins. Methods Enzymol 568:303-50 |
| Hobbs, Ryan P; DePianto, Daryle J; Jacob, Justin T et al. (2015) Keratin-dependent regulation of Aire and gene expression in skin tumor keratinocytes. Nat Genet 47:933-8 |
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