644 Lysosomes support the degradation, signaling, and mitochondrial metabolism necessary for human epidermal differentiation

Abstract

Keratinocytes undergo significant structural remodeling during epidermal differentiation, including a broad transformation of the proteome coupled with a reduction in total cellular biomass. This suggests that intracellular digestion of proteins and organelles is necessary for keratinocyte differentiation. Here, we use both genetic and pharmacologic approaches to demonstrate that lysosomal function and autophagy are both required for keratinocyte differentiation in organotypic human skin. Lysosomal activity was required for mTOR signaling and mitochondrial oxidative metabolism. In turn, mitochondrial reactive oxygen species (mtROS), produced as a natural byproduct of oxidative phosphorylation, were necessary for keratinocyte differentiation. Finally, treatment with exogenous ROS rescued the differentiation defect in lysosome-inhibited keratinocytes. These findings highlight a reciprocal relationship between lysosomes and mitochondria, in which lysosomes support mitochondrial metabolism and the associated production of mtROS. The mtROS released to the cytoplasm in suprabasal keratinocytes triggers autophagy and lysosome-mediated degradation necessary for epidermal differentiation. As defective lysosome dependent autophagy is associated with common skin diseases including psoriasis and atopic dermatitis, a better understanding of the role of lysosomes in epidermal homeostasis may guide future therapeutic strategies.

Control of cell death‐associated danger signals during cornification prevents autoinflammation of the skin

“…Nuclear DNA is degraded by DNase1L2 and DNase 2 and RNases are likely to degrade mRNAs and other RNA species. Although the precise regulation and order of degradative events remain to be determined, a critical role of lysosomes in cornification can be assumed . In particular, the involvement of the lysosomal DNase 2 suggests that the content of lysosomes (including a multitude of degradative enzymes) is released to the cytoplasm and also gains access to components of the nucleus.…”