Yang Li, Meng Xu, Xiao Ding, Chen Yan, Zhiqin Song, Lianwan Chen, Xiahe Huang, Xin Wang, Youli Jian, Guihua Tang, Changyong Tang, Yingtong Di, Shuzhen Mu, Xuezhao Liu, Kai Liu, Ting Li, Yingchun Wang, Long Miao, Weixiang Guo, Xiaojiang Hao & Chonglin Yang
Nature Cell Biology
2016 vol: 18 pp: 1065–1077 doi: 10.1038/ncb3407
Lysosomes respond to environmental cues by controlling their own biogenesis, but the underlying mechanisms are poorly understood. Here we describe a protein kinase C (PKC)-dependent and mTORC1-independent mechanism for regulating lysosome biogenesis, which provides insights into previously reported effects of PKC on lysosomes. By identifying lysosome-inducing compounds we show that PKC couples activation of the TFEB transcription factor with inactivation of the ZKSCAN3 transcriptional repressor through two parallel signalling cascades. Activated PKC inactivates GSK3β, leading to reduced phosphorylation, nuclear translocation and activation of TFEB, while PKC activates JNK and p38 MAPK, which phosphorylate ZKSCAN3, leading to its inactivation by translocation out of the nucleus. PKC activation may therefore mediate lysosomal adaptation to many extracellular cues. PKC activators facilitate clearance of aggregated proteins and lipid droplets in cell models and ameliorate amyloid β plaque formation in APP/PS1 mouse brains. Thus, PKC activators are viable treatment options for lysosome-related disorders.
Topics: Cell signalling, Lysosomes, Membrane trafficking, Organelles, Aromatic compounds, Detergents, Enzymes, Fusion proteins, Small molecules, Supplements, Monolith – MicroScale Thermophoresis, MST, Proteins, Publications