Smurf2, an E3 ubiquitin ligase, interacts with PDE4B and attenuates liver fibrosis through miR-132 mediated CTGF inhibition
Smurf2, an E3 ubiquitin ligase, interacts with PDE4B and attenuates liver fibrosis through miR-132 mediated CTGF inhibition
复制标题
Smurf2 是一种 E3 泛素连接酶，与 PDE4B 相互作用，并通过 miR-132 介导的 CTGF 抑制来减轻肝纤维化。
DOI：
10.1016/j.bbamcr.2017.10.011
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发表时间：
2018-02-01
影响因子：
5.1
通讯作者：
Zhang, Si
中科院分区：
文献类型：
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作者：
Cai, Yu;Huang, Guanqun;Zhang, Si
我们以前报道过，Smad泛素调节因子2（Smurf 2）的活性在人类肝纤维化中降低。在这里，我们在转基因小鼠的肝脏中过表达Smurf 2，并在四氯化碳治疗或胆管结扎诱导的纤维化模型中观察到抑制胶原沉积和肝星状细胞活化。肝Smurf 2过表达也抑制了结缔组织生长因子（CTGF）的产生，CTGF是肝纤维化的中心介质。使用miRNA阵列和生物信息学分析，我们确定了miR-132作为这种抑制作用的介质。miR-132直接靶向CTGF的3 '-非翻译区，并通过cAMP-PKA-CREB信号传导转录上调。此外，Smurf 2通过与磷酸二酯酶4 B（PDE 4 B）相互作用并促进其降解而激活cAMP-PKA-CREB通路。因此，我们已经证明了一种以前未被认识到的由Smurf 2控制的抗纤维化途径。
We previously reported that Smad ubiquitin regulatory factor 2 (Smurf2) activity was decreased in human fibrotic livers. Here, we overexpressed Smurf2 in livers of transgenic mice and observed inhibited collagen deposition and hepatic stellate cell activation in fibrotic model induced by carbon tetrachloride treatment or bile duct ligation. Hepatic Smurf2 overexpression also inhibited the production of connective tissue growth factor (CTGF), a central mediator of liver fibrosis. Using miRNA array and bioinformatics analyses, we identified miR-132 as a mediator of this inhibitory effect. miR-132 directly targets the 3'-untranslated region of CTGF and was transcriptionally upregulated by cAMP-PKA-CREB signaling. In addition, Smurf2 activated cAMP-PKA-CREB pathway by interacting with phosphodiesterase 4B (PDE4B) and facilitating its degradation. Thus, we have demonstrated a previously unrecognized anti-fibrotic pathway controlled by Smurf2.