PARP-1 Controls the Adipogenic Transcriptional Program by PARylating C/EBPβ and Modulating Its Transcriptional Activity.
PARP-1 Controls the Adipogenic Transcriptional Program by PARylating C/EBPβ and Modulating Its Transcriptional Activity.
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PARP-1通过加倍C/EBPβ并调节其转录活性来控制脂肪的转录程序。
DOI：
10.1016/j.molcel.2016.11.015
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发表时间：
2017-01-19
期刊：
影响因子：
16
通讯作者：
Kraus WL
中科院分区：
文献类型：
--
作者：
Luo X;Ryu KW;Kim DS;Nandu T;Medina CJ;Gupte R;Gibson BA;Soccio RE;Yu Y;Gupta RK;Kraus WL
Poly(ADP-ribosyl)ation （PARylation）是PARP家族成员介导的蛋白质翻译后修饰，如PARP-1。尽管PARylation已被广泛研究，但很少有关于位点特异性PARylation的明确生物学作用的报道。在这里，我们发现C/EBPβ，一个关键的促脂肪转录因子，在一个保守的调节区域被PARP-1在三个氨基酸上聚合。在各种遗传和细胞模型中，这些位点的PARylation抑制C/EBPβ的DNA结合和转录活性，并减弱脂肪形成。有趣的是，PARP-1的催化活性在分化的前48小时急剧下降，这与parylation介导的抑制释放C/EBPβ相对应。这促进了C/EBPβ增强子的结合，控制脂肪生成靶基因的表达和持续分化。PARP-1的消耗或化学抑制，或C/EBPβ上PARP-1化位点的突变，增强了这些早期的脂肪形成事件。总的来说，我们的结果提供了一个明确的例子，说明位点特异性PARylation如何驱动生物学结果。Luo等人的研究表明，PARP-1通过在其调节区域的三个残基上与C/EBPβ（一种促脂肪转录因子）结合，从而减缓脂肪的形成。这些残基的突变产生parp -1抗性超活性转录因子，在缺乏激素诱导剂的情况下促进脂肪形成。
Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification of proteins mediated by PARP family members, such as PARP-1. Although PARylation has been studied extensively, few examples of definitive biological roles for site-specific PARylation have been reported. Here we show that C/EBPβ, a key pro-adipogenic transcription factor, is PARylated by PARP-1 on three amino acids in a conserved regulatory domain. PARylation at these sites inhibits C/EBPβ’s DNA binding and transcriptional activities, and attenuates adipogenesis in various genetic and cell-based models. Interestingly, PARP-1 catalytic activity drops precipitously during the first 48 hours of differentiation, corresponding to a release of C/EBPβ from PARylation-mediated inhibition. This promotes the binding of C/EBPβ at enhancers controlling the expression of adipogenic target genes and continued differentiation. Depletion or chemical inhibition of PARP-1, or mutation of the PARylation sites on C/EBPβ, enhances these early adipogenic events. Collectively, our results provide a clear example of how site-specific PARylation drives biological outcomes. Luo et al. show that PARP-1 attenuates adipogenesis by PARylating C/EBPβ, a proadipogenic transcription factor, on three residues in its regulatory domain. Mutation of these residues produces a PARP-1-resistant superactive transcription factor that promotes adipogenesis in the absence of hormonal inducers.