Jang Y H, Choi K Y, Min D S
Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Korea.
Translational Research Center for Protein Function Control, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
Cell Death Differ. 2014 Apr;21(4):533-46. doi: 10.1038/cdd.2013.174. Epub 2013 Dec 6.
Autophagy is a catabolic process in which cell components are degraded to maintain cellular homeostasis by nutrient limitations. Defects of autophagy are involved in numerous diseases, including cancer. Here, we demonstrate a new role of phospholipase D (PLD) as a regulator of autophagy. PLD inhibition enhances autophagic flux via ATG1 (ULK1), ATG5 and ATG7, which are essential autophagy gene products critical for autophagosome formation. Moreover, PLD suppresses autophagy by differentially modulating phosphorylation of ULK1 mediated by mTOR and adenosine monophosphate-activated protein kinase (AMPK), and by suppressing the interaction of Beclin 1 with vacuolar-sorting protein 34 (Vps34), indicating that PLD coordinates major players of the autophagic pathway, AMPK-mTOR-ULK1 and Vps34/Beclin 1. Ultimately, PLD inhibition significantly sensitized in vitro and in vivo cancer regression via genetic and pharmacological inhibition of autophagy, providing rationale for a new therapeutic approach to enhancing the anticancer efficacy of PLD inhibition. Collectively, we show a novel role for PLD in the molecular machinery regulating autophagy.
自噬是一种分解代谢过程，在该过程中细胞成分被降解以通过营养限制维持细胞内稳态。自噬缺陷与包括癌症在内的多种疾病有关。在此，我们证明了磷脂酶D（PLD）作为自噬调节因子的新作用。PLD抑制通过自噬相关基因1（ATG1，即ULK1）、自噬相关基因5（ATG5）和自噬相关基因7（ATG7）增强自噬通量，这些是自噬体形成所必需的关键自噬基因产物。此外，PLD通过差异调节由雷帕霉素靶蛋白（mTOR）和腺苷酸活化蛋白激酶（AMPK）介导的ULK1磷酸化，以及通过抑制Beclin 1与液泡分选蛋白34（Vps34）的相互作用来抑制自噬，这表明PLD协调自噬途径的主要参与者，即AMPK - mTOR - ULK1和Vps34/Beclin 1。最终，通过对自噬的基因和药理学抑制，PLD抑制在体外和体内均显著增强了癌症消退，为增强PLD抑制的抗癌疗效提供了一种新的治疗方法的理论依据。总体而言，我们展示了PLD在调节自噬的分子机制中的新作用。
