K16 as a novel regulator of Nrf2 function in glabrous skin: Implications for pachyonychia congenita and its treatment
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The painful palmoplantar keratoderma (PPK) arising in individuals with pachyonychia congenita (PC) exhibit a significant upregulation of danger-associated molecular patterns and skin barrier regulators. Mice null for keratin 16 (Krt16), one of the genes mutated in PC, faithfully reproduce the morphological and molecular features of PC-associated PPK. We show here that onset of PPK is preceded by oxidative stress in male Krt16-/- mouse footpad skin, correlating with an inability of keratinocytes to sustain Nrf2-dependent expression of enzymes involved in the synthesis of the cellular antioxidant glutathione (GSH). Hypoactivity of Nrf2 coincides with impaired PKCδ activity and reduced levels of RACK1 protein in Krt16-/- footpad skin. Topical application of the small-molecule Nrf2 activator sulforaphane (SF) in male Krt16-/- mice prevents the development of PPK alongside a normalization of redox balance via the stimulation of GSH reductase and regeneration of GSH from existing cellular pools. Relative to males, female Krt16-/- mice exhibit faulty responsiveness to SF treatment. Preliminary data suggests that dual treatment of footpad skin with SF and selective estrogen receptor β agonist diarylpropionitrile (DPN) prevents the development of PPK lesions in female Krt16-/- mice. These findings point to oxidative stress and hypoactive Nrf2 as contributors to the pathogenesis of PC-related PPK and identify K16 as a regulator of the RACK1-PKCδ-NRF2 axis in skin keratinocytes. This pathway appears to be more complex in female Krt16-/- mice due to fundamental sex-based differences and, specifically, to a significant contribution of estrogen receptor signaling to modulation of Nrf2 function in skin keratinocytes. Our findings suggest a potential avenue to treat PC-associated PPK and may extend to similar keratin-based disorders.