TY - JOUR
T1 - ZKSCAN3 Is a Master Transcriptional Repressor of Autophagy
AU - Chauhan, Santosh
AU - Goodwin, Jinesh G.
AU - Chauhan, Swati
AU - Manyam, Ganiraju
AU - Wang, Jing
AU - Kamat, Ashish M.
AU - Boyd, Douglas D.
N1 - Funding Information:
We are grateful to Drs. Ralph Nixon and Josef Mautner for providing the LC3-DsRed and GFP-Neo plasmids, respectively. We are grateful to Dr. Andrea Ballabio for providing TFEB-overexpressing HeLa cells and Flag-TFEB plasmid. We acknowledge Mr. Kenneth Dunner, Jr., at High Resolution Electron Microscopy Facility at UTMDACC for performing SEM and TEM. This work was supported by National Institutes of Health grant R01CA58311 (to D.D.B.).
PY - 2013/4/11
Y1 - 2013/4/11
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2013.01.024
DO - 10.1016/j.molcel.2013.01.024
M3 - Article
C2 - 23434374
AN - SCOPUS:84876090708
SN - 1097-2765
VL - 50
SP - 16
EP - 28
JO - Molecular cell
JF - Molecular cell
IS - 1
ER -