Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2.
Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2.
复制标题
线粒体 PKM2 通过稳定 Bcl2 来调节氧化应激诱导的细胞凋亡。
DOI：
10.1038/cr.2016.159
复制
发表时间：
2017-03
期刊：
影响因子：
44.1
通讯作者：
Yang W
中科院分区：
文献类型：
--
作者：
Liang J;Cao R;Wang X;Zhang Y;Wang P;Gao H;Li C;Yang F;Zeng R;Wei P;Li D;Li W;Yang W
丙酮酸激酶M2异构体（Pyruvate kinase M2 isoform, PKM2）催化糖酵解的最后一步，在肿瘤细胞增殖中起重要作用。最近的研究报道PKM2也调节细胞凋亡。然而，PKM2的作用机制尚不清楚。在这里，我们发现PKM2在氧化应激下易位到线粒体。在线粒体中，PKM2与Bcl2相互作用并使其苏氨酸(T) 69位点磷酸化。这种磷酸化阻止了基于cul3的E3连接酶与Bcl2的结合和随后的Bcl2降解。PKM2的这一功能需要一种伴侣蛋白HSP90α1。HSP90α1的atp酶活性引发PKM2的构象变化，促进PKM2与Bcl2的相互作用。在原位异种移植模型中，用磷酸化缺陷的Bcl2 T69A突变体替代野生型Bcl2使胶质瘤细胞对氧化应激诱导的凋亡敏感，并损害脑肿瘤的形成。值得注意的是，一个由PKM2的389到405氨基酸残基组成的肽，PKM2通过它与Bcl2结合，破坏PKM2与Bcl2的相互作用，促进Bcl2降解，损害脑肿瘤的生长。此外，在人类胶质母细胞瘤患者标本中，Bcl2 T69磷酸化水平、构象改变的PKM2和Bcl2蛋白相互关联。此外，Bcl2 T69磷酸化水平和构象改变的PKM2水平与恶性胶质瘤的分级和预后相关。我们的研究结果揭示了线粒体PKM2磷酸化Bcl2并直接抑制细胞凋亡的新机制，强调了PKM2在癌细胞ROS适应中的重要作用，并暗示HSP90-PKM2-Bcl2轴是胶质母细胞瘤治疗干预的潜在靶点。
Pyruvate kinase M2 isoform (PKM2) catalyzes the last step of glycolysis and plays an important role in tumor cell proliferation. Recent studies have reported that PKM2 also regulates apoptosis. However, the mechanisms underlying such a role of PKM2 remain elusive. Here we show that PKM2 translocates to mitochondria under oxidative stress. In the mitochondria, PKM2 interacts with and phosphorylates Bcl2 at threonine (T) 69. This phosphorylation prevents the binding of Cul3-based E3 ligase to Bcl2 and subsequent degradation of Bcl2. A chaperone protein, HSP90α1, is required for this function of PKM2. HSP90α1's ATPase activity launches a conformational change of PKM2 and facilitates interaction between PKM2 and Bcl2. Replacement of wild-type Bcl2 with phosphorylation-deficient Bcl2 T69A mutant sensitizes glioma cells to oxidative stress-induced apoptosis and impairs brain tumor formation in an orthotopic xenograft model. Notably, a peptide that is composed of the amino acid residues from 389 to 405 of PKM2, through which PKM2 binds to Bcl2, disrupts PKM2-Bcl2 interaction, promotes Bcl2 degradation and impairs brain tumor growth. In addition, levels of Bcl2 T69 phosphorylation, conformation-altered PKM2 and Bcl2 protein correlate with one another in specimens of human glioblastoma patients. Moreover, levels of Bcl2 T69 phosphorylation and conformation-altered PKM2 correlate with both grades and prognosis of glioma malignancy. Our findings uncover a novel mechanism through which mitochondrial PKM2 phosphorylates Bcl2 and inhibits apoptosis directly, highlight the essential role of PKM2 in ROS adaptation of cancer cells, and implicate HSP90-PKM2-Bcl2 axis as a potential target for therapeutic intervention in glioblastoma.