BNIP3 plays crucial roles in the differentiation and maintenance of epidermal keratinocytes

Keratinization of the stratum corneum involves a highly choreographed sequence of events in which granular cells lose their nuclei and become desiccated corneocytes. Akinduro et al. detail the molecular machinery underlying removal of the nucleus (nucleophagy) during the final stages of keratinization. They provide evidence that nucleophagy is induced when the keratinocytes differentiate and that failure in the initiation of nucleophagy is associated with parakeratosis.

Section: Autophagy-related Genes In Epidermissupporting

confidence: 92%

Nucleophagy: A New Look at Past Observations

Han

Lavker

2016

“…Decreased iASPP expression in keratinocytes not only triggers autophagy by derepression of the ATG5/ATG12-ATG16L1 complex, promoting autophagosome maturation, but also induces terminal differentiation. Likewise, another elegant study has recently highlighted the importance of BNIP3 in inducing autophagy but also terminal differentiation of epidermal keratinocytes (Moriyama et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Constitutive Autophagy and Nucleophagy during Epidermal Differentiation

Akinduro

Sully

Patel

et al. 2016

168

201

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.

“…Keratinocyte differentiation also involves organelle clearance and recycling of cellular components. Recent studies revealed that autophagy is directly involved in this process (Belleudi et al, 2014;Moriyama et al, 2014). Interestingly, the Drosophila SNAP29 homolog ubisnap mediates fusion of autophagosomes with endosomes/lysosomes (Takats et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Establishment of Two Mouse Models for CEDNIK Syndrome Reveals the Pivotal Role of SNAP29 in Epidermal Differentiation

Schiller

Seebode

Wieser

et al. 2016

Loss-of-function mutations in the synaptosomal-associated protein 29 (SNAP29) gene cause the cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome. In this study, we created total (Snap29(-/-)) as well as keratinocyte-specific (Snap29(fl/fl)/K14-Cre) Snap29 knockout mice. Both mutant mice exhibited a congenital distinct ichthyotic phenotype resulting in neonatal lethality. Mutant mice revealed acanthosis and hyperkeratosis as well as abnormal keratinocyte differentiation and increased proliferation. In addition, the epidermal barrier was severely impaired. These results indicate an essential role of SNAP29 in epidermal differentiation and barrier formation. Markedly decreased deposition of lamellar body contents in mutant mice epidermis and the observation of malformed lamellar bodies indicate severe impairments in lamellar body function due to the Snap29 knockout. We also found increased microtubule associated protein-1 light chain 3, isoform B-II levels, unchanged p62/SQSTM1 protein amounts, and strong induction of the endoplasmic reticulum stress marker C/EBP homologous protein in mutant mice. This emphasizes a role of SNAP29 in autophagy and endoplasmic reticulum stress. Our murine models serve as powerful tools for investigating keratinocyte differentiation processes and provide insights into the essential contribution of SNAP29 to epidermal differentiation.