Zhang Yajuan, Zhao Ming, Gao Hong, Yu Guanzhen, Zhao Yun, Yao Feng, Yang Weiwei
State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Medical Artificial Intelligence Laboratory, Zhejiang Institute of Digital Media, Chinese Academy of Science, Shaoxing, China.
Nat Metab. 2022 Mar;4(3):374-388. doi: 10.1038/s42255-022-00543-7. Epub 2022 Mar 21.
Tumour cells utilize multiple strategies to evade the immune system, but the underlying metabolic mechanisms remain poorly understood. The pyruvate dehydrogenase (PDH) complex converts pyruvate to acetyl-coenzyme A in mitochondria, thereby linking glycolysis to the ricarboxylic acid cycle. Here we show that the PDH complex E1 subunit α (PDHE1α) is also located in the cytosol. Cytosolic PDHE1α interacts with IKKβ and protein phosphatase 1B, thereby facilitating the inhibition of the NF-κB pathway. Cytosolic PDHE1α can be phosphorylated at S327 by ERK2 and translocated into mitochondria. Decreased cytosolic PDHE1α levels restore NF-κB signalling, whereas increased mitochondrial PDHE1α levels drive α-ketoglutarate production and promote reactive oxygen species detoxification. Synergistic activation of NF-κB and reactive oxygen species detoxification promotes tumour cell survival and enhances resistance to cytotoxic lymphocytes. Consistently, low levels of PDHE1α phosphorylation are associated with poor prognosis of patients with lung cancer. Our findings show a mechanism through which phosphorylation-dependent subcellular translocation of PDHE1α promotes tumour immune evasion.
肿瘤细胞利用多种策略逃避免疫系统，但其潜在的代谢机制仍知之甚少。丙酮酸脱氢酶（PDH）复合物在线粒体中将丙酮酸转化为乙酰辅酶A，从而将糖酵解与三羧酸循环联系起来。在此，我们表明PDH复合物E1亚基α（PDHE1α）也位于细胞质中。细胞质中的PDHE1α与IKKβ和蛋白磷酸酶1B相互作用，从而促进对NF-κB途径的抑制。细胞质中的PDHE1α可在S327位点被ERK2磷酸化并转运至线粒体。细胞质中PDHE1α水平的降低可恢复NF-κB信号传导，而线粒体中PDHE1α水平的升高则驱动α-酮戊二酸的产生并促进活性氧解毒。NF-κB和活性氧解毒的协同激活促进肿瘤细胞存活并增强对细胞毒性淋巴细胞的抗性。一致地，PDHE1α磷酸化水平低与肺癌患者的不良预后相关。我们的研究结果显示了一种机制，通过该机制，PDHE1α的磷酸化依赖性亚细胞易位促进肿瘤免疫逃逸。
