Nucleophagy: A New Look at Past Observations

Abstract

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.

Figure 1.

A keratinocyte in an advanced stage of transformation from a granular cell to a corneocyte. Lysosomes/autophagosomes (L) are present in the cytoplasm. Filaggrin (K) is spread throughout the cytoplasm intermingling with keratin filaments (F). The thickened, modified corneocyte envelope (PM) is tightly attached to the lower granular cell. The nucleus (N), last of the recognizable organelles, shows signs of degradation. Reprinted from ©Lavker and Matoltsy, 1970, J Cell Biology, 44:501–512

Figure 2.

Autophagy and its initiation. (A) A schematic representation of the stages of autophagy. (B) A schematic representation of the initial steps in autophagy involving the formation of an isolation membrane. In this process, unc-51 like autophagy activating kinase 1 (ULK1) complex activates the phosphatidylinositol-3-kinase (PI3K) complex (VPS34/Beclin1/ATG14L). VPS34-derived PI3P recruits double FYVE-containing protein 1 (DFCP1/ZFYVE1) and WD repeat domain phosphoinositide interacting 1 (WIPI1) to the outer membrane of autophagosomes, which causes the association of the ATG5/ATG12 conjugate with ATG16L1. The ATG5/ATG12/ATG16L1 complex then adds phosphatidylethanolamine group (PE) to the C-terminus of the microtubule associated protein 1 light chain 3 (LC3) protein promoting the elongation of the isolation membrane and autophagosome formation.