Wei Yongjie, Pattingre Sophie, Sinha Sangita, Bassik Michael, Levine Beth
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Mol Cell. 2008 Jun 20;30(6):678-88. doi: 10.1016/j.molcel.2008.06.001.
Starvation induces autophagy to preserve cellular homeostasis in virtually all eukaryotic organisms. However, the mechanisms by which starvation induces autophagy are not completely understood. In mammalian cells, the antiapoptotic protein, Bcl-2, binds to Beclin 1 during nonstarvation conditions and inhibits its autophagy function. Here we show that starvation induces phosphorylation of cellular Bcl-2 at residues T69, S70, and S87 of the nonstructured loop; Bcl-2 dissociation from Beclin 1; and autophagy activation. In contrast, viral Bcl-2, which lacks the phosphorylation site-containing nonstructured loop, fails to dissociate from Beclin 1 during starvation. Furthermore, the stress-activated signaling molecule, c-Jun N-terminal protein kinase 1 (JNK1), but not JNK2, mediates starvation-induced Bcl-2 phosphorylation, Bcl-2 dissociation from Beclin 1, and autophagy activation. Together, our findings demonstrate that JNK1-mediated multisite phosphorylation of Bcl-2 stimulates starvation-induced autophagy by disrupting the Bcl-2/Beclin 1 complex. These findings define a mechanism that cells use to regulate autophagic activity in response to nutrient status.
饥饿几乎在所有真核生物中都会诱导自噬以维持细胞内稳态。然而，饥饿诱导自噬的机制尚未完全明确。在哺乳动物细胞中，抗凋亡蛋白Bcl-2在非饥饿条件下与Beclin 1结合并抑制其自噬功能。在此我们表明，饥饿会诱导细胞Bcl-2在非结构化环的T69、S70和S87位点发生磷酸化；Bcl-2与Beclin 1解离；以及自噬激活。相比之下，缺乏含磷酸化位点的非结构化环的病毒Bcl-2在饥饿期间无法与Beclin 1解离。此外，应激激活信号分子c-Jun氨基末端蛋白激酶1（JNK1）而非JNK2介导饥饿诱导的Bcl-2磷酸化、Bcl-2与Beclin 1解离以及自噬激活。总之，我们的研究结果表明，JNK1介导的Bcl-2多位点磷酸化通过破坏Bcl-2/Beclin 1复合物刺激饥饿诱导的自噬。这些发现定义了一种细胞用于根据营养状态调节自噬活性的机制。
