2. Academic Validation
  3. MAPK13 phosphorylates PHGDH and promotes its degradation via chaperone-mediated autophagy during liver injury

MAPK13 phosphorylates PHGDH and promotes its degradation via chaperone-mediated autophagy during liver injury

  • Cell Discov. 2025 Feb 18;11(1):15. doi: 10.1038/s41421-024-00758-w.
Ru Xing # 1,  Ruilong Liu # 2,  Yongxiao Man # 1,  Chen Liu 1,  Yajuan Zhang 3,  Hong Gao 1,  Weiwei Yang 4 5
Affiliations

Affiliations

  • 1 Key Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 2 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
  • 3 Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Key Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. wyang@sibcb.ac.cn.
  • 5 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China. wyang@sibcb.ac.cn.
  • # Contributed equally.
PMID: 39962071 DOI: 10.1038/s41421-024-00758-w
Abstract

Drug-induced liver injury (DILI) is the leading cause of acute liver failure and poses a significant clinical challenge in both diagnosis and treatment. Serine synthesis pathway (SSP) links glycolysis to one-carbon cycle and plays an important role in cell homeostasis by regulating substance synthesis, redox homeostasis and gene expression. However, the regulatory mechanism of SSP in DILI remains unclear. Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting Enzyme in SSP. Here we show that during DILI, mitogen-activated protein kinase 13 (MAPK13) is activated and then phosphorylates PHGDH at serine 371 upon oxidative stress, which triggers PHGDH protein degradation via chaperone-mediated Autophagy (CMA) pathway. PHGDH degradation suppresses SSP and glutathione production, thereby exacerbating DILI and cholestatic liver injury. Importantly, both MAPK13 inhibition and dietary serine supplementation ameliorates these liver injuries. Our finding demonstrates a unique regulatory mechanism of SSP, in which MAPK13 phosphorylates PHGDH and promotes its CMA degradation, establishes its critical role in DILI and cholestatic liver injury, and highlights the therapeutic potential of MAPK13 Inhibitor or dietary serine to treat these liver injuries.

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