Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India.
Unilever R&D, Bangalore, 560066, India.
Cell Death Dis. 2019 Mar 19;10(4):269. 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 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.
角朊细胞通过细胞分化维持表皮完整性。这个过程增强了角朊细胞的细胞器内消化，以维持在上皮层观察到的营养和钙离子应激。然而，控制角朊细胞分化和伴随的溶酶体功能增加的分子机制还知之甚少。在这里，我们使用原代新生儿人表皮角朊细胞，确定了信号通路和细胞分化/溶酶体发生之间的分子联系。用 CaCl2 孵育角朊细胞可诱导分化，细胞体积增大，早期分化标志物增加。此外，分化的角朊细胞显示出增强的溶酶体发生，这是通过 ATF6 依赖性 ER 应激信号产生的，但独立于 mTOR-MiT/TFE 途径。相比之下，化学抑制 mTORC1 加速钙诱导的角朊细胞分化，表明自噬的激活促进了分化过程。此外，角朊细胞的分化导致溶酶体分散和高尔基体碎片化，周边溶酶体与高尔基体连接蛋白共定位，表明这些细胞器可能来源于高尔基体。同样，高尔基体功能的抑制，但不是高尔基体连接蛋白的耗尽或溶酶体酸度的改变，会阻止角朊细胞的分化和溶酶体发生。因此，ER 应激调节溶酶体发生和角朊细胞分化，以维持表皮的内稳态。
