Protein kinase C controls lysosome biogenesis independently of mTORC1

被引：272

作者：

Li, Yang ^{[1
]}

Xu, Meng ^{[1
,2
]}

Ding, Xiao ^{[3
,5
]}

Yan, Chen ^{[4
,5
]}

Song, Zhiqin ^{[4
]}

Chen, Lianwan ^{[6
]}

Huang, Xiahe ^{[1
]}

Wang, Xin ^{[1
]}

Jian, Youli ^{[1
]}

Tang, Guihua ^{[3
]}

Tang, Changyong ^{[1
]}

Di, Yingtong ^{[3
]}

Mu, Shuzhen ^{[4
,5
]}

Liu, Xuezhao ^{[1
,2
]}

Liu, Kai ^{[1
,2
]}

Li, Ting ^{[1
]}

Wang, Yingchun ^{[1
]}

Miao, Long ^{[6
]}

Guo, Weixiang ^{[1
]}

Hao, Xiaojiang ^{[3
,4
,5
]}

Yang, Chonglin ^{[1
]}

机构：

[1] Chinese Acad Sci, Inst Genet & Dev Biol, State Key Lab Mol Dev Biol, 1 West Beichen Rd, Beijing 100101, Peoples R China

[2] Chinese Acad Sci, Grad Univ, Beijing 100039, Peoples R China

[3] Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources Western, Kunming 650021, Peoples R China

[4] Key Lab Chem Nat Prod Guizhou Prov, Guiyang 550002, Peoples R China

[5] Chinese Acad Sci, Guiyang 550002, Peoples R China

[6] Chinese Acad Sci, Inst Biophys, Beijing Key Lab Noncoding RNA, Key Lab RNA Biol, 15 Datun Rd, Beijing 100101, Peoples R China

来源：

NATURE CELL BIOLOGY | 2016年 / 18卷 / 10期

基金：

美国国家科学基金会;

关键词：

ANTIGEN-PRESENTATION; TFEB; AUTOPHAGY; ACTIVATION; INHIBITION; CLEARANCE; DEGRADATION; MECHANISMS; CASCADES; SIGNALS;

D O I：

10.1038/ncb3407

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 GSK3 beta, 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 beta plaque formation in APP/PS1 mouse brains. Thus, PKC activators are viable treatment options for lysosome-related disorders.

引用

页码：1065 / 1077

页数：13

共 47 条

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