2. Academic Validation
  3. MAPK signalling-induced phosphorylation and subcellular translocation of PDHE1α promotes tumour immune evasion

MAPK signalling-induced phosphorylation and subcellular translocation of PDHE1α promotes tumour immune evasion

  • Nat Metab. 2022 Mar;4(3):374-388. doi: 10.1038/s42255-022-00543-7.
Yajuan Zhang  # 1,  Ming Zhao  # 1,  Hong Gao 1,  Guanzhen Yu 2,  Yun Zhao 3 4,  Feng Yao 5,  Weiwei Yang 6 7
Affiliations

Affiliations

  • 1 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.
  • 2 Medical Artificial Intelligence Laboratory, Zhejiang Institute of Digital Media, Chinese Academy of Science, Shaoxing, China.
  • 3 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. [email protected].
  • 4 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
  • 5 Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. [email protected].
  • 6 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. [email protected].
  • 7 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 35315437 DOI: 10.1038/s42255-022-00543-7
Abstract

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.

Figures
Products
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  • HY-15947
    99.75%, ERK Inhibitor
    ERK