RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells
RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells
复制标题
RNA结合蛋白ZFP36/TTP通过调节肝星状细胞自噬信号通路预防铁死亡
DOI：
10.1080/15548627.2019.1687985
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发表时间：
2019-11-13
期刊：
影响因子：
13.3
通讯作者：
Zheng, Shizhong
中科院分区：
文献类型：
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作者：
Zhang, Zili;Guo, Mei;Zheng, Shizhong
铁下垂是最近发现的一种程序性细胞死亡形式，但其调控机制仍然知之甚少。在这里，我们发现rna结合蛋白ZFP36/TTP （ZFP36无名指蛋白）在调节肝星状细胞（hsc）中起着至关重要的作用。暴露于诱导铁凋亡的化合物后，泛素连接酶FBXW7/CDC4（含7的F-box和WD重复结构域）通过识别SFSGLPS基序降低ZFP36蛋白的表达。FBXW7质粒促进了经典的铁凋亡事件，而ZFP36质粒则破坏了FBXW7质粒诱导的HSC铁凋亡。有趣的是，ZFP36质粒通过破坏ATG16L1（自噬相关16 like 1） mRNA的稳定性来抑制巨噬/自噬激活。ATG16L1质粒消除了ZFP36质粒对铁凋亡的抑制作用，FBXW7质粒增强了ATG16L1质粒对自噬的抑制作用。重要的是，ZFP36质粒通过与3MODIFIER LETTER prime - untranslation区域的富au元件（AREs）结合，促进了ATG16L1 mRNA的衰变。ARE区域的内部突变消除了ZFP36介导的ATG16L1 mRNA的不稳定性，并阻止了ZFP36质粒介导的铁凋亡抗性。在小鼠中，用erastin和sorafenib治疗通过诱导HSC铁下垂来减轻小鼠肝纤维化。HSC特异性过表达Zfp36会损害erastin或sorafenib诱导的HSC铁凋亡。值得注意的是，我们分析了索拉非尼对接受索拉非尼单药治疗的肝细胞癌纤维化患者HSC铁下垂的影响。引人注目的是，索拉非尼单药治疗导致人类hsc中ZFP36下调、铁蛋白自噬激活和铁凋亡诱导。总的来说，这些结果揭示了铁下垂的新分子机制和信号通路，并确定了zfp36 -自噬依赖性铁下垂作为治疗肝纤维化的潜在靶点。
Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms remain poorly understood. Here, we show that the RNA-binding protein ZFP36/TTP (ZFP36 ring finger protein) plays a crucial role in regulating ferroptosis in hepatic stellate cells (HSCs). Upon exposure to ferroptosis-inducing compounds, the ubiquitin ligase FBXW7/CDC4 (F-box and WD repeat domain containing 7) decreased ZFP36 protein expression by recognizing SFSGLPS motif. FBXW7 plasmid contributed to classical ferroptotic events, whereas ZFP36 plasmid impaired FBXW7 plasmid-induced HSC ferroptosis. Interestingly, ZFP36 plasmid inhibited macroautophagy/autophagy activation by destabilizing ATG16L1 (autophagy related 16 like 1) mRNA. ATG16L1 plasmid eliminated the inhibitory action of ZFP36 plasmid on ferroptosis, and FBXW7 plasmid enhanced the effect of ATG16L1 plasmid on autophagy. Importantly, ZFP36 plasmid promoted ATG16L1 mRNA decay via binding to the AU-rich elements (AREs) within the 3MODIFIER LETTER PRIME-untranslated region. The internal mutation of the ARE region abrogated the ZFP36-mediated ATG16L1 mRNA instability, and prevented ZFP36 plasmid-mediated ferroptosis resistance. In mice, treatment with erastin and sorafenib alleviated murine liver fibrosis by inducing HSC ferroptosis. HSC-specific overexpression of Zfp36 impaired erastin- or sorafenib-induced HSC ferroptosis. Noteworthy, we analyzed the effect of sorafenib on HSC ferroptosis in fibrotic patients with hepatocellular carcinoma receiving sorafenib monotherapy. Attractively, sorafenib monotherapy led to ZFP36 downregulation, ferritinophagy activation, and ferroptosis induction in human HSCs. Overall, these results revealed novel molecular mechanisms and signaling pathways of ferroptosis, and also identified ZFP36-autophagy-dependent ferroptosis as a potential target for the treatment of liver fibrosis.