ZKSCAN3 is a master transcriptional repressor of autophagy

Mol Cell. 2013 Apr 11;50(1):16-28. doi: 10.1016/j.molcel.2013.01.024. Epub 2013 Feb 21.

Abstract

Autophagy constitutes a major cell-protective mechanism that eliminates damaged components and maintains energy homeostasis via recycling nutrients under normal/stressed conditions. Although the core components of autophagy have been well studied, regulation of autophagy at the transcriptional level is poorly understood. Herein, we establish ZKSCAN3, a zinc finger family DNA-binding protein, as a transcriptional repressor of autophagy. Silencing of ZKSCAN3 induced autophagy and increased lysosome biogenesis. Importantly, we show that ZKSCAN3 represses transcription of a large gene set (>60) integral to, or regulatory for, autophagy and lysosome biogenesis/function and that a subset of these genes, including Map1lC3b and Wipi2, represent direct targets. Interestingly, ZKSCAN3 and TFEB are oppositely regulated by starvation and in turn oppositely regulate lysosomal biogenesis and autophagy, suggesting that they act in conjunction. Altogether, our study uncovers an autophagy master switch regulating the expression of a transcriptional network of genes integral to autophagy and lysosome biogenesis/function.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Autophagy* / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Carrier Proteins / metabolism
  • Cell Shape
  • Cellular Senescence
  • Energy Metabolism
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Lysosomes / metabolism*
  • Lysosomes / pathology
  • Membrane Proteins / metabolism
  • Microtubule-Associated Proteins / metabolism
  • Phosphate-Binding Proteins
  • RNA Interference
  • Signal Transduction
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic*
  • Transfection

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Carrier Proteins
  • MAP1LC3B protein, human
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Phosphate-Binding Proteins
  • TFEB protein, human
  • Transcription Factors
  • WIPI-2 protein, human
  • ZKSCAN3 protein, human