Keratinocyte differentiation promotes ER stress-dependent lysosome biogenesis

• Published in: Cell death & disease Vol. 10; no. 4; p. 269
• Main Authors: Mahanty, Sarmistha, Dakappa, Shruthi Shirur, Shariff, Rezwan, Patel, Saloni, Swamy, Mruthyunjaya Mathapathi, Majumdar, Amitabha, Setty, Subba Rao Gangi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.03.2019; Springer Nature B.V
• Subjects: 13/106; 13/89; 14/63; 38/22; 631/443/810; 631/80/642/1624; 631/80/86/1999; 96/1; 96/106; 96/95; Acidity; Activating Transcription Factor 6 - genetics; Activating Transcription Factor 6 - metabolism; ADP-Ribosylation Factors; Antibodies; Autophagy; Autophagy - drug effects; Autophagy - genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Biochemistry; Biomedical and Life Sciences; Biosynthesis; Calcium - pharmacology; Calcium chloride; Cell Biology; Cell Culture; Cell Differentiation; Cell size; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - physiology; Epidermal Cells - cytology; Epidermal Cells - metabolism; Golgi apparatus; Golgi Apparatus - drug effects; Golgi Apparatus - metabolism; Homeostasis; Humans; Immunology; Keratinocytes; Keratinocytes - cytology; Keratinocytes - drug effects; Keratinocytes - metabolism; Life Sciences; Lysosomes; Lysosomes - enzymology; Lysosomes - metabolism; Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors; Mechanistic Target of Rapamycin Complex 1 - genetics; Mechanistic Target of Rapamycin Complex 1 - metabolism; Microphthalmia-Associated Transcription Factor - genetics; Microphthalmia-Associated Transcription Factor - metabolism; Molecular modelling; Neonates; Organelles; Phagocytosis; Signal transduction; Signal Transduction - genetics; Skin; Skin - cytology; Skin - metabolism; TOR protein
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1478-4

Keratinocytes maintain epidermal integrity through cellular differentiation. This process enhances intraorganelle digestion in keratinocytes to sustain nutritional and calcium-ionic stresses observed in upper skin layers. However, the molecular mechanisms governing keratinocyte differentiation and concomitant increase in lysosomal function is poorly understood. Here, by using primary neonatal human epidermal keratinocytes, we identified the molecular link between signaling pathways and cellular differentiation/lysosome biogenesis. Incubation of keratinocytes with CaCl 2 induces differentiation with increased cell size and early differentiation markers. Further, differentiated keratinocytes display enhanced lysosome biogenesis generated through ATF6-dependent ER stress signaling, but independent of mTOR-MiT/TFE pathway. In contrast, chemical inhibition of mTORC1 accelerates calcium-induced keratinocyte differentiation, suggesting that activation of autophagy promotes the differentiation process. Moreover, differentiation of keratinocytes results in lysosome dispersion and Golgi fragmentation, and the peripheral lysosomes showed colocalization with Golgi-tethering proteins, suggesting that these organelles possibly derived from Golgi. In line, inhibition of Golgi function, but not the depletion of Golgi-tethers or altered lysosomal acidity, abolishes keratinocyte differentiation and lysosome biogenesis. Thus, ER stress regulates lysosome biogenesis and keratinocyte differentiation to maintain epidermal homeostasis. Lysosomes are the key digestive organelles of differentiated keratinocytes in the epidermis. Mahanty et al. show that ER stress but not mTOR-MiT/TFE factors promotes lysosome biogenesis during keratinocyte differentiation, which is critical for epidermal homeostasis.