Constitutive Autophagy and Nucleophagy during Epidermal Differentiation

J Invest Dermatol. 2016 Jul;136(7):1460-1470. doi: 10.1016/j.jid.2016.03.016. Epub 2016 Mar 25.

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.

MeSH terms

  • Animals
  • Animals, Newborn
  • Autophagy*
  • Cell Differentiation
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Epidermis / embryology
  • Epidermis / physiology*
  • Humans
  • Keratinocytes / cytology*
  • Lamin Type A / metabolism
  • Lamin Type B / metabolism
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Microtubule-Associated Proteins / metabolism*
  • Multiprotein Complexes / metabolism
  • Phagosomes / metabolism
  • Psoriasis / pathology
  • Skin / metabolism
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Lamin Type A
  • Lamin Type B
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • lamin B1
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1