Watanabe Yukihide, Papoutsoglou Panagiotis, Maturi Varun, Tsubakihara Yutaro, Hottiger Michael O, Heldin Carl-Henrik, Moustakas Aristidis
From Ludwig Cancer Research, Science for Life Laboratory, Uppsala University, SE-751 24 Uppsala, Sweden.
the Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland, and.
J Biol Chem. 2016 Jun 10;291(24):12706-12723. doi: 10.1074/jbc.M116.729699. Epub 2016 Apr 21.
We previously established a mechanism of negative regulation of transforming growth factor β signaling mediated by the nuclear ADP-ribosylating enzyme poly-(ADP-ribose) polymerase 1 (PARP1) and the deribosylating enzyme poly-(ADP-ribose) glycohydrolase (PARG), which dynamically regulate ADP-ribosylation of Smad3 and Smad4, two central signaling proteins of the pathway. Here we demonstrate that the bone morphogenetic protein (BMP) pathway can also be regulated by the opposing actions of PARP1 and PARG. PARG positively contributes to BMP signaling and forms physical complexes with Smad5 and Smad4. The positive role PARG plays during BMP signaling can be neutralized by PARP1, as demonstrated by experiments where PARG and PARP1 are simultaneously silenced. In contrast to PARG, ectopic expression of PARP1 suppresses BMP signaling, whereas silencing of endogenous PARP1 enhances signaling and BMP-induced differentiation. The two major Smad proteins of the BMP pathway, Smad1 and Smad5, interact with PARP1 and can be ADP-ribosylated in vitro, whereas PARG causes deribosylation. The overall outcome of this mode of regulation of BMP signal transduction provides a fine-tuning mechanism based on the two major enzymes that control cellular ADP-ribosylation.
我们先前建立了一种由核ADP-核糖基化酶聚（ADP-核糖）聚合酶1（PARP1）和去核糖基化酶聚（ADP-核糖）糖苷水解酶（PARG）介导的转化生长因子β信号负调控机制，它们动态调节该信号通路的两个核心信号蛋白Smad3和Smad4的ADP-核糖基化。在此我们证明，骨形态发生蛋白（BMP）信号通路也可受PARP1和PARG的相反作用调控。PARG对BMP信号起正向作用，并与Smad5和Smad4形成物理复合物。PARG在BMP信号传导过程中发挥的正向作用可被PARP1抵消，这在PARG和PARP1同时沉默的实验中得到了证明。与PARG相反，PARP1的异位表达抑制BMP信号，而内源性PARP1的沉默则增强信号及BMP诱导的分化。BMP信号通路的两个主要Smad蛋白Smad1和Smad5与PARP1相互作用，并且在体外可被ADP-核糖基化，而PARG则导致去核糖基化。这种BMP信号转导调控模式的总体结果提供了一种基于控制细胞ADP-核糖基化的两种主要酶的微调机制。
