Protein kinase C controls lysosome biogenesis independently of mTORC1

Nat Cell Biol. 2016 Oct;18(10):1065-77. doi: 10.1038/ncb3407. Epub 2016 Sep 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Nucleus / metabolism
  • Lysosomes / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Metabolic Networks and Pathways
  • Mice
  • Multiprotein Complexes / metabolism*
  • Phosphorylation
  • Protein Kinase C / metabolism*
  • Protein Transport / physiology
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcription Factors / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Multiprotein Complexes
  • Transcription Factors
  • ZKSCAN3 protein, mouse
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Protein Kinase C
  • p38 Mitogen-Activated Protein Kinases