Abstract
SummaryAutophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations. In the case of starvation, a signaling cascade involving AMPK and histone deacetylase SIRT1 displaces chromatin-bound BRD4, instigating autophagy gene activation and cell survival. Importantly, this program is directed independently and also reciprocally to the growth-promoting properties of BRD4 and is potently repressed by BRD4-NUT, a driver of NUT midline carcinoma. These findings therefore identify a distinct and selective mechanism of autophagy regulation.
Highlights
Autophagy is initiated by the formation of double-membraned structures called phagophores that originate from endoplasmic reticulum (ER)-derived omegasomes as well as other sources (Ktistakis and Tooze, 2016)
Bromodomain-containing protein 4 (BRD4) Is a Repressor of Autophagy To understand the regulatory mechanisms of autophagy, we conducted an RNAi screen using Drosophila S2R+ cells stably expressing GFP-LC3 (Wilkinson et al, 2011)
To validate the screening results, we knocked down the genes encoding BRD2, BRD3, or BRD4 in human pancreatic ductal adenocarcinoma KP-4 cells and determined their effects on autophagy by monitoring the levels of the lipidated form of LC3 (LC3II)—a marker of autophagosome formation/accumulation (Klionsky et al, 2016)
Summary
Autophagy is initiated by the formation of double-membraned structures called phagophores that originate from endoplasmic reticulum (ER)-derived omegasomes as well as other sources (Ktistakis and Tooze, 2016). As phagophores grow, they form sphere-like structures called autophagosomes that sequester and entrap cytoplasmic components. Intensive studies have identified the genes involved in the various steps of autophagy, which has led to an established basic machinery for this complicated vesicular trafficking system (Ktistakis and Tooze, 2016; Lamb et al, 2013)
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