Akinduro Olufolake, Sully Katherine, Patel Ankit, Robinson Deborah J, Chikh Anissa, McPhail Graham, Braun Kristin M, Philpott Michael P, Harwood Catherine A, Byrne Carolyn, O'Shaughnessy Ryan F L, Bergamaschi Daniele
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.
EM Service, Blizard Institute Pathology Core Facility, Cellular Pathology Department, Royal London Hospital, London, UK.
J Invest Dermatol. 2016 Jul;136(7):1460-1470. doi: 10.1016/j.jid.2016.03.016. Epub 2016 Mar 25.
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.
表皮角质形成细胞通过表皮迁移至颗粒层，在终末分化时，它们逐渐失去细胞器并转变为无核细胞或角质形成细胞。我们的报告探讨了自噬在确保表皮功能中的作用，提供了发育中表皮自噬标志物表达的首个全面概况。我们发现自噬在表皮颗粒层中持续活跃，通过电子显微镜我们鉴定出了双膜自噬体。我们证明分化的角质形成细胞经历了一种选择性核自噬形式，其特征是微管相关蛋白轻链3/溶酶体相关膜蛋白2/p62阳性自噬溶酶体的积累。这些核周囊泡对组蛋白相互作用蛋白、异染色质蛋白1α呈阳性，并定位于与核纤层蛋白A和B1积累相邻的位置，而在新生小鼠和成人皮肤中，我们报告在颗粒层内LC3斑点与畸形核重合。这一过程依赖于自噬的完整性，这一点通过从WD重复结构域磷酸肌醇相互作用蛋白1或Unc-51样自噬激活激酶1中耗尽的分化角质形成细胞中缺乏核自噬得到证实。在皮肤疾病模型中的最终验证表明，自噬受损有助于银屑病的发病机制。银屑病皮肤病变中LC3表达的缺乏与角化不全以及大多数自噬标志物的表达或定位失调相关。我们的发现可能对表皮屏障缺陷患者具有启示意义并改善治疗选择。
