Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function.
Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function.
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DOI：
10.1016/j.molcel.2017.04.027
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发表时间：
2017-05-18
期刊：
影响因子：
16
通讯作者：
Ryan KM
中科院分区：
文献类型：
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作者：
Sakamaki JI;Wilkinson S;Hahn M;Tasdemir N;O'Prey J;Clark W;Hedley A;Nixon C;Long JS;New M;Van Acker T;Tooze SA;Lowe SW;Dikic I;Ryan KM
自噬是一种指导溶酶体中细胞质物质降解的膜运输过程。这一过程促进了细胞的保真度，虽然自噬的核心机制是已知的，但促进和维持自噬的机制却不太清楚。在这里，我们报道表观遗传解读器BRD4和甲基转移酶G9a抑制TFEB/TFE3/ mitf独立的转录程序，促进自噬和溶酶体的生物发生。我们发现BRD4敲低诱导自噬在体外和体内响应一些，但不是全部，情况。在饥饿的情况下，涉及AMPK和组蛋白去乙酰化酶SIRT1的信号级联取代染色质结合的BRD4，诱导自噬基因激活和细胞存活。重要的是，该程序是独立的，也相互作用于BRD4的生长促进特性，并被BRD4-NUT （NUT中线癌的驱动因素）有效抑制。因此，这些发现确定了一种独特的选择性自噬调节机制。BRD4抑制一个独立于MiT/TFE的自噬程序和溶酶体基因。BRD4去抑制促进某些类型的自噬，但不促进其他类型的自噬。营养剥夺通过AMPK信号通路去抑制BRD4以促进细胞存活。癌蛋白BRD4- nut是自噬和溶酶体功能的有效抑制因子。Sakamaki等人表明BRD4抑制自噬和溶酶体基因表达。在营养剥夺过程中，这种抑制通过AMPK-SIRT1信号传导得到缓解，从而允许自噬激活。BRD4抑制增强自噬通量和溶酶体功能，促进蛋白质聚集体的降解。
Autophagy 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. BRD4 represses a program of autophagy and lysosome genes independently of MiT/TFE BRD4 de-repression promotes certain types of autophagy, but not others Nutrient deprivation de-represses BRD4 via AMPK signaling to promote cell survival Oncoprotein BRD4-NUT is a potent repressor of autophagy and lysosome function Sakamaki et al. show that BRD4 represses autophagy and lysosome gene expression. This repression is alleviated during nutrient deprivation through AMPK-SIRT1 signaling, allowing autophagy activation. BRD4 inhibition enhances autophagic flux and lysosomal function and promotes the degradation of protein aggregates.