Constitutive autophagy and nucleophagy during epidermal differentiation

Epidermal keratinocytes migrate through the epidermis up to the granular layer where, upon terminal differentiation they progressively loose organelles and convert into anucleate cells or corneocytes. Our report explores the role of autophagy in ensuring epidermal function providing the first comprehensive profile of autophagy marker expression in developing epidermis. We show that autophagy is constitutively active in epidermal granular layer where by electron microscopy we identified double membrane-autophagosomes. We demonstrate that differentiating keratinocytes undergo a selective form of nucleophagy characterized by accumulation of LC3/LAMP2/p62 positive autolysosomes. These perinuclear vesicles displayed positivity for histone interacting protein HP1α and localize in proximity with Lamin A and B1 accumulation, while in newborn mice and adult human skin we report LC3 puncta coincident with misshaped nuclei within the granular layer. This process relies on autophagy integrity as confirmed by lack of nucleophagy in differentiating keratinocytes depleted from WIPI1 or ULK1. Final validation into a skin disease model showed that impaired autophagy contributes to the pathogenesis of psoriasis. Lack of LC3 expression in psoriatic skin lesions correlates with parakeratosis and deregulated expression or location of most of the autophagic markers. Our findings may have implications and improve treatment options for patients with epidermal barrier defects