Ni, Zhenhong He, Jintao Wu, Yaran Hu, Changjiang Dai, Xufang Yan, Xiaojing Li, Bo Li, Xinzhe Xiong, Haojun Li, Yuming Li, Song Xu, Liang Li, Yongsheng Lian, Jiqin He, Fengtian AKT-mediated phosphorylation of ATG4B impairs mitochondrial activity and enhances the Warburg effect in hepatocellular carcinoma cells <p>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, it is still unknown as to the role of ATG4B phosphorylation in cancers. 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<sub>1</sub>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<sub>1</sub>Fo-ATP synthase in HCC cells. Furthermore, recombinant human ATG4B protein suppressed the activity of F<sub>1</sub>Fo-ATP synthase in MgATP submitochondrial particles from patient-derived HCC tissues <i>in vitro</i>. 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<sub>1</sub>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.</p> AKT;ATG4B;F1Fo-ATP synthase;HCC;phosphorylation;Warburg effect 2017-11-22
    https://tandf.figshare.com/articles/dataset/AKT-mediated_phosphorylation_of_ATG4B_impairs_mitochondrial_activity_and_enhances_the_Warburg_effect_in_hepatocellular_carcinoma_cells/5625097
10.6084/m9.figshare.5625097.v1