Protein kinase C controls lysosome biogenesis independently of mTORC1.
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.
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, No.1 West Beichen Road, Chaoyang District, Beijing 100101, China.
Yang
Y
Li
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, No.1 West Beichen Road, Chaoyang District, Beijing 100101, China.|Graduate University of Chinese Academy of Sciences, Beijing 100039, China.
Meng
M
Xu
State Key Laboratory of Phytochemistry and Plant Resources in Western China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650021, China.
Xiao
X
Ding
The Key Laboratory of Chemistry for Natural Product of Guizhou Province and Chinese Academy of Science, Guiyang 550002, China.
Chen
C
Yan
The Key Laboratory of Chemistry for Natural Product of Guizhou Province and Chinese Academy of Science, Guiyang 550002, China.
Zhiqin
Z
Song
Key Laboratory of RNA Biology, Beijing Key Laboratory of Noncoding RNA, Institute of Biophysics, Chinese Academy of Sciences, No.15 Datun Road, Chaoyang District, Beijing 100101, China.
Lianwan
L
Chen
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, No.1 West Beichen Road, Chaoyang District, Beijing 100101, China.
Xiahe
X
Huang
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, No.1 West Beichen Road, Chaoyang District, Beijing 100101, China.
Xin
X
Wang
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, No.1 West Beichen Road, Chaoyang District, Beijing 100101, China.
Youli
Y
Jian
State Key Laboratory of Phytochemistry and Plant Resources in Western China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650021, China.
Guihua
G
Tang
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, No.1 West Beichen Road, Chaoyang District, Beijing 100101, China.
Changyong
C
Tang
State Key Laboratory of Phytochemistry and Plant Resources in Western China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650021, China.
Yingtong
Y
Di
The Key Laboratory of Chemistry for Natural Product of Guizhou Province and Chinese Academy of Science, Guiyang 550002, China.
Shuzhen
S
Mu
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, No.1 West Beichen Road, Chaoyang District, Beijing 100101, China.|Graduate University of Chinese Academy of Sciences, Beijing 100039, China.
Xuezhao
X
Liu
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, No.1 West Beichen Road, Chaoyang District, Beijing 100101, China.|Graduate University of Chinese Academy of Sciences, Beijing 100039, China.
Kai
K
Liu
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, No.1 West Beichen Road, Chaoyang District, Beijing 100101, China.
Ting
T
Li
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, No.1 West Beichen Road, Chaoyang District, Beijing 100101, China.
Yingchun
Y
Wang
Key Laboratory of RNA Biology, Beijing Key Laboratory of Noncoding RNA, Institute of Biophysics, Chinese Academy of Sciences, No.15 Datun Road, Chaoyang District, Beijing 100101, China.
Long
0000-0002-0562-6681
L
Miao
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, No.1 West Beichen Road, Chaoyang District, Beijing 100101, China.
Weixiang
W
Guo
State Key Laboratory of Phytochemistry and Plant Resources in Western China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650021, China.|The Key Laboratory of Chemistry for Natural Product of Guizhou Province and Chinese Academy of Science, Guiyang 550002, China.
Xiaojiang
X
Hao
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, No.1 West Beichen Road, Chaoyang District, Beijing 100101, China.
Chonglin
C
Yang
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D053858:Metabolic Networks and Pathways; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D046912:Multiprotein Complexes; D014157:Transcription Factors; C535120:ZKSCAN3 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases