Research in the Coulombe laboratory focuses on the regulation of cell differentiation and tissue homeostasis in complex epithelia such as skin, which we study from the perspective of keratin intermediate filament genes and proteins. A major role of keratin filaments is to endow epithelial cells and tissues with the ability to withstand mechanical and other forms of stresses. Genetic mutations that affect the primary structure of individual keratin proteins compromise this role and underlie several inherited blistering diseases in which epithelial cells are rendered fragile and rupture readily upon exposure to physical stress. We study the biochemical and structural determinants of this vital role, and are pursuing novel approaches to treat keratin-based genetic diseases. A newly defined role for keratins is to bind and modulate the activity of a variety of regulators and signaling effectors, with a significant impact on homeostasis in complex epithelia. Thus we have found that keratins impact the survival, growth, and architecture of keratinocytes in skin epithelia, and that such contributions can be critically important during wound repair, in the lifelong growth cycle of hair follicles, and in the context of cancer, psoriasis, and related diseases. Also, the laboratory discovered a role for keratin proteins in the regulation of protein synthesis and epithelial cell growth, and in the regulation of inflammation and innate and acquired immunity, in skin tissue. More recently, we discovered that keratin proteins occur in the nucleus, whey they are bound the promoter of specific genes that they help regulate in the setting of chronic inflammatory skin disease and cancer, and participate in the regulation of the redox balance in skin keratinocytes. We are interested in assessing whether targeting keratin expression could be beneficial in such chronic diseases.
Kerns ML, Hakim JM, Lu RG, Guo Y, Berroth A, Kaspar RL, Coulombe PA. Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes. J Clin Invest. 2016 PMID: 27183391.
Hobbs RP, Batazzi AS, Han MC, Coulombe PA. Loss of Keratin 17 induces tissue-specific cytokine polarization and cellular differentiation in HPV16-driven cervical tumorigenesis in vivo. Oncogene. 2016 PMID: 27065324.
Hobbs RP, DePianto DJ, Jacob JT, Han MC, Chung BM, Batazzi AS, Poll BG, Guo Y, Han J, Ong S, Zheng W, Taube JM, Čiháková D, Wan F, Coulombe PA.
Keratin-dependent regulation of Aire and gene expression in skin tumor keratinocytes. Nat Genet. 2015 PMID: 26168014.
Chung BM, Arutyunov A, Ilagan E, Yao N, Wills-Karp M, Coulombe PA. Regulation of C-X-C chemokine gene expression by keratin 17 and hnRNP K in skin tumor keratinocytes. J Cell Biol. 2015 PMID: 25713416.
Depianto D, Kerns ML, Dlugosz AA, Coulombe PA. Keratin 17 promotes epithelial proliferation and tumor growth by polarizing the immune response in skin. Nat Genet. 2010 PMID: 20871598.