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Protein kinase C controls lysosome biogenesis independently of mTORC1.

Abstract：

: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.

journal_name

Nat Cell Biol

journal_title

Nature cell biology

authors

Li Y,Xu M,Ding X,Yan C,Song Z,Chen L,Huang X,Wang X,Jian Y,Tang G,Tang C,Di Y,Mu S,Liu X,Liu K,Li T,Wang Y,Miao L,Guo W,Hao X,Yang C

doi

10.1038/ncb3407

subject

Has Abstract

pub_date

2016-10-01 00:00:00

pages

1065-77

issue

10

eissn

1465-7392

issn

1476-4679

pii

ncb3407

journal_volume

18

pub_type

杂志文章

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