AKT-mediated phosphorylation of ATG4B impairs mitochondrial activity and enhances the Warburg effect in hepatocellular carcinoma cells
AKT-mediated phosphorylation of ATG4B impairs mitochondrial activity and enhances the Warburg effect in hepatocellular carcinoma cells
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AKT 介导的 ATG4B 磷酸化会损害线粒体活性并增强肝细胞癌细胞中的 Warburg 效应。
DOI：
10.1080/15548627.2017.1407887
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发表时间：
2018-01-01
期刊：
影响因子：
13.3
通讯作者：
He, Fengtian
中科院分区：
文献类型：
--
作者：
Ni, Zhenhong;He, Jintao;He, Fengtian
磷酸化修饰是一种重要的翻译后修饰形式，可影响细胞的生理功能。ATG 4 B是一种重要的自噬/自噬相关蛋白，对肿瘤细胞的存活具有潜在的影响。然而，ATG 4 B磷酸化在癌症中的作用仍然未知。在本研究中，我们在肝癌细胞中发现了一个新的ATG 4 B的Ser 34磷酸化位点。ATG 4 B丝氨酸34位的磷酸化对肝癌细胞自噬流量影响不大，但能促进肝癌细胞L-乳酸生成和葡萄糖消耗增加，氧消耗减少的瓦尔堡效应。ATG 4 B的Ser 34磷酸化还导致肝癌细胞线粒体活性的损害，包括F（1）Fo-ATP合酶活性的抑制和线粒体ROS的升高。此外，ATG 4 B在Ser 34位的磷酸化增强了其在肝癌细胞线粒体中的定位以及随后与F（1）Fo-ATP合酶的共定位。此外，重组人ATG 4 B蛋白在体外抑制来自患者来源的HCC组织的MgATP亚线粒体颗粒中的F（1）Fo-ATP合酶的活性。总之，我们的研究结果首次表明，ATG 4 B在Ser 34位的磷酸化通过抑制线粒体功能参与了HCC细胞的代谢重编程，这可能是由于Ser 34磷酸化诱导的ATG 4 B线粒体富集和随后的F（1）Fo-ATP合酶活性抑制。我们的研究结果揭示了ATG 4 B在病理条件下的非经典工作模式，这可能为通过靶向ATG 4 B及其Ser 34磷酸化来开发新的肝癌治疗策略提供科学依据。
Phosphorylation is a major type of post-translational modification, which can influence the cellular physiological function. ATG4B, a key macroautophagy/autophagy-related protein, has a potential effect on the survival of tumor cells. However, the role of ATG4B phosphorylation in cancers is still unknown. In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells. The phosphorylation of ATG4B at Ser34 had little effect on autophagic flux, but promoted the Warburg effect including the increase of L-lactate production and glucose consumption, and the decrease of oxygen consumption in HCC cells. The Ser34 phosphorylation of ATG4B also contributed to the impairment of mitochondrial activity including the inhibition of F(1)Fo-ATP synthase activity and the elevation of mitochondrial ROS in HCC cells. Moreover, the phosphorylation of ATG4B at Ser34 enhanced its mitochondrial location and the subsequent colocalization with F(1)Fo-ATP synthase in HCC cells. Furthermore, recombinant human ATG4B protein suppressed the activity of F(1)Fo-ATP synthase in MgATP submitochondrial particles from patient-derived HCC tissues in vitro. In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F(1)Fo-ATP synthase activity. Our findings reveal a noncanonical working pattern of ATG4B under pathological conditions, which may provide a scientific basis for developing novel strategies for HCC treatment by targeting ATG4B and its Ser34 phosphorylation.