Journal Article

Protein kinase C controls lysosome biogenesis independently of mTORC1

Chen, Lianwan, Yang, Chonglin, Wang, Xin, Ding, Xiao, Yan, Chen, Hao, Xiaojiang, Huang, Xiahe, Liu, Kai, Jian, Youli, Tang, Changyong, Di, Yingtong, Liu, Xuezhao, Wang, Yingchun, Miao, Long, Mu, Shuzhen, Guo, Weixiang, Song, Zhiqin, Li, Ting, Li, Yang, Tang, Guihua, Xu, Meng

2016

Overview

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. Using a chemical screening approach, Yang and colleagues identify PKC as a regulator of lysosome biogenesis, which controls the subcellular localization of TFEB and ZKSCAN3 through parallel signalling pathways and independently of mTORC1.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/106 / 14/1 / 14/19 / 14/28 / 14/34 / 14/35 / 38/109 / 38/77 / 38/88 / 38/89 / 38/90 / 631/80/313 / 631/80/642 / 631/80/642/1624 / 631/80/86 / 82/58 / 82/80 / 82/83 / 96/31 / 96/44 / 96/95 / Animals / Autophagy / Biosynthesis / Cancer Research / Cell Biology / Cell Nucleus - metabolism / Cytological research / Developmental Biology / Inactivation / Kinases / Laboratories / Life Sciences / Lysosomes / Lysosomes - metabolism / Mechanistic Target of Rapamycin Complex 1 / Metabolic Networks and Pathways / Mice / Multiprotein Complexes - metabolism / p38 Mitogen-Activated Protein Kinases - metabolism / Phosphorylation / Physiological aspects / Protein Kinase C - metabolism / Protein kinases / Protein Transport - physiology / Proteins / Stem Cells / TOR Serine-Threonine Kinases - metabolism / Transcription factors / Transcription Factors - metabolism / Translocation