ZKSCAN3 Is a Master Transcriptional Repressor of Autophagy

Abstract

Summary Autophagy constitutes a major cell protective mechanism eliminating damaged components and maintaining energy homoeostasis 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 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.

The AMPK-PPARGC1A pathway is required for antimicrobial host defense through activation of autophagy

“…Several transcription factors and molecules have been reported to induce or regulate the transcription of autophagy genes in various steps of autophagy and lysosome biogenesis. [48][49][50] Our data provide evidence that PPARGC1A, induced by AICAR-induced AMPK activation, triggers antimicrobial activity, of which at least one mechanism is the CEBPB-mediated induction of autophagy genes to induce antibacterial autophagy. It has been shown that increased PPARGC1A expression is strictly dependent on the binding of CEBPB to the proximal PPARGC1A promoter in 3T3-L1 preadipocytes.…”

A large-scale analysis of autophagy-related gene expression identifies new regulators of autophagy

“…18 In higher eukaryotes the family of FOXO transcription factors, GATA1 as well as the master regulator TFEB, activate autophagy, [19][20][21] while ZKSCAN3 and GATA4 are involved in the repression of mammalian autophagy-related genes. [22][23] In yeast, recent studies characterized Ume6 and Pho23 as transcriptional repressors of ATG genes and negative regulators of autophagy. 24,17 Nevertheless, very few transcription factors involved in the regulation of the expression of ATG genes in either yeast or mammals are known.…”

Regulation of lysosome biogenesis and functions in osteoclasts

“…Interestingly, it was recently shown that the transcription factor ZKSCAN3 inhibits lysosomal biogenesis in HeLa cells. 97 Whether a pathway counteracting TFEB also exists in osteoclasts is not known, but one can speculate that the tight control of the balance between this putative pathway and TFEB will be critical to bone mass maintenance.…”