Manipulating PML SUMOylation via Silencing UBC9 and RNF4 Regulates Cardiac Fibrosis
Manipulating PML SUMOylation via Silencing UBC9 and RNF4 Regulates Cardiac Fibrosis
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通过沉默 UBC9 和 RNF4 操纵 PML SUMO 化调节心脏纤维化
DOI：
10.1016/j.ymthe.2016.12.021
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发表时间：
2017-03-01
影响因子：
12.4
通讯作者：
Chu, Wen-Feng
中科院分区：
文献类型：
--
作者：
Liu, Yu;Zhao, Dan;Chu, Wen-Feng
早幼粒细胞白血病蛋白 (PML) 在称为 PML 核体 (PML-NB) 的动态亚核结构的组装中至关重要，该结构参与调节多种细胞功能。然而，PML 与心脏病有关的可能性尚未得到检验。在接受横主动脉缩窄 (TAC) 和三氧化二砷 (ATO) 注射的小鼠中，转化生长因子 β 1 (TGF-β 1) 随着 PML SUMO 化的动态变化而上调。在培养的新生小鼠心脏成纤维细胞 (NMCF) 中，ATO、血管紧张素 II (Ang II) 和胎牛血清 (FBS) 显着触发 PML SUMO 化和 PML-NB 的组装。通过沉默 UBC9（一种独特的 SUMO E2 结合酶）来抑制 SUMO 化的 PML，可减少 TAC 小鼠心脏纤维化的发展并部分改善心脏功能。相反，通过沉默 RNF4（一种多 SUMO 特异性 E3 泛素连接酶）来增强 SUMO 化的 PML 积累，可加速诱导心脏纤维化并促进与 Pinl（Pinl 的正调节因子）共定位的心脏功能损伤。 TGF-（PML-NB 中的 β 1 mRNA 表达）和 TGF-β 1 活性增加这些发现表明，UBC9/PML/RNF4 轴作为重要的 SUMO 通路在心脏纤维化中发挥着关键作用，调节该通路的蛋白水平为治疗心脏纤维化和心力衰竭提供了一个有吸引力的治疗靶点。
The promyelocytic leukemia protein (PML) is essential in the assembly of dynamic subnuclear structures called PML nuclear bodies (PML-NBs), which are involved in regulating diverse cellular functions. However, the possibility of PML being involved in cardiac disease has not been examined. In mice undergoing transverse aortic constriction (TAC) and arsenic trioxide (ATO) injection, transforming growth factor beta 1 (TGF-(beta 1) was upregulated along with dynamic alteration of PML SUMOylation. In cultured neonatal mouse cardiac fibroblasts (NMCFs), ATO, angiotensin II (Ang II), and fetal bovine serum (FBS) significantly triggered PML SUMOylation and the assembly of PML-NBs. Inhibition of SUMOylated PML by silencing UBC9, the unique SUMO E2-conjugating enzyme, reduced the development of cardiac fibrosis and partially improved cardiac function in TAC mice. In contrast, enhancing SUMOylated PML accumulation, by silencing RNF4, a poly-SUMO-specific E3 ubiquitin ligase, accelerated the induction of cardiac fibrosis and promoted cardiac function injury. PML colocalized with Pinl (a positive regulator for TGF-(beta 1 mRNA expression in PML-NBs) and increased TGF-beta 1 activity. These findings suggest that the UBC9/PML/RNF4 axis plays a critical role as an important SUMO pathway in cardiac fibrosis. Modulating the protein levels of the pathway provides an attractive therapeutic target for the treatment of cardiac fibrosis and heart failure.