title: Constitutive Autophagy and Nucleophagy during Epidermal Differentiation.
abstract: Epidermal keratinocytes migrate through the epidermis up to the granular layer where, on terminal differentiation, they progressively lose 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 the 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 microtubule-associated protein light chain 3/lysosomal-associated membrane protein 2/p62 positive autolysosomes. These perinuclear vesicles displayed positivity for histone interacting protein, heterochromatin protein 1α, and localize in proximity with Lamin A and B1 accumulation, whereas 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 WD repeat domain phosphoinositide interacting 1 or Unc-51 like autophagy activating kinase 1. 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.
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Olufolake
authors.initials: O
authors.lastname: Akinduro
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Sully
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Ankit
authors.initials: A
authors.lastname: Patel
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Robinson
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Anissa
authors.initials: A
authors.lastname: Chikh
authors.affiliation: EM Service, Blizard Institute Pathology Core Facility, Cellular Pathology Department, Royal London Hospital, London, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: McPhail
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Braun
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Philpott
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Harwood
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Byrne
authors.affiliation: Livingstone Skin Research Centre for Children, UCL Institute of Child Health, London, UK; Department of Immunobiology, UCL Institute of Child Health, London, UK.
authors.forename: Ryan F L
authors.initials: RFL
authors.lastname: O'Shaughnessy
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. Electronic address: d.bergamaschi@qmul.ac.uk.
authors.forename: Daniele
authors.initials: D
authors.lastname: Bergamaschi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004817:Epidermis / Q000196:embryology / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology*; D034904:Lamin Type A / Q000378:metabolism; D034921:Lamin Type B / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D011565:Psoriasis / Q000473:pathology; D012867:Skin / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D034904:Lamin Type A; D034921:Lamin Type B; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases