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PHGDH/SYK: a hub integrating anti-fungal immunity and serine metabolism

Cell Death & Differentiation (2024)Cite this article

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Abstract

Immune cells modify their metabolic pathways in response to fungal infections. Nevertheless, the biochemical underpinnings need to be better understood. This study reports that fungal infection drives a switch from glycolysis to the serine synthesis pathway (SSP) and one-carbon metabolism by inducing the interaction of spleen tyrosine kinase (SYK) and phosphoglycerate dehydrogenase (PHGDH). As a result, PHGDH promotes SYK phosphorylation, leading to the recruitment of SYK to C-type lectin receptors (CLRs). The CLR/SYK complex initiates signaling cascades that lead to transcription factor activation and pro-inflammatory cytokine production. SYK activates SSP and one-carbon metabolism by inducing PHGDH activity. Then, one-carbon metabolism supports S-adenosylmethionine and histone H3 lysine 36 trimethylation to drive the production of pro-inflammatory cytokines and chemokines. These findings reveal the crosstalk between amino acid metabolism, epigenetic modification, and CLR signaling during fungal infection.

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Fig. 1: Fungal infections drive glucose flux from glycolysis to the SSP and one-carbon metabolism.
Fig. 2: The SSP, one-carbon metabolism, and SAM are required for anti-fungal innate immunity.
Fig. 3: SYK associates with PHGDH.
Fig. 4: PHGDH is indispensable for anti-fungal immunity.
Fig. 5: SYK is indispensable for fungal-regulated metabolism.
Fig. 6: Exogenous methionine and serine corporately support fungal-induced inflammation by fueling SAM generation.
Fig. 7: SAM generation and methylation reactions coordinately modulate histone methylation marks during fungal-induced inflammation.
Fig. 8: Immunometabolites in the PPP, the SSP, and one-carbon metabolism correlate with inflammatory factor expression in fungal-infected patients.
Fig. 9: The synergistic effects of the PPP, the SSP, the folate cycle, and the methionine cycle on SAM generation and inflammatory regulation in the context of fungal infection.

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Data availability

The original contributions presented in the study are included in the article or the supplementary material. This paper does not report original code. Other data that support the findings are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the National Key Research and Development Program of China (2021YFC2701800, 2021YFC2701804), the Fundamental Research Funds for the Central Universities (2042022dx0003), the Fundamental Research Funds for the Central Universities (2042021kf023), the National Natural Science Foundation of China (81872262) and Deutsche Forschungsgemeinschaft (Transregio TRR60).

Author information

Author notes

  1. These authors contributed equally: Xinyong Zhang, Dongdong Hu, Xiaoyan Sun

Authors and Affiliations

  1. Department of Neurology, The Second People’s Hospital of Huai ‘an, Huai ‘an, 223001, China

    Xinyong Zhang & Yong Zhou

  2. Department of Emergency, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210031, China

    Dongdong Hu

  3. School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan, 316022, China

    Xiaoyan Sun

  4. The Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, and Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China

    Yichun Gu & Aidong Chen

  5. The Key Laboratory of Targeted Intervention of Clinical Disease, University Hospital Essen, University of Duisburg-Essen, Essen, 45122, Germany

    Chuanxin Su

  6. State Key Laboratory of Virology, Modern Virology Research Center, Frontier Science Center for Immunology and Metabolism, College of Life Sciences, Wuhan University, Wuhan, 430072, China

    Shi Liu

  7. Department of Critical Care Medicine, Children’s Hospital of Fudan University, Shanghai, China

    Caiyan Zhang & Guoping Lu

  8. Department of Laboratory Medicine, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China

    Qiwen Wu

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Contributions

QWW and ADC conceived and designed the experiment. XYY, DDH, XYS,YCG and YZ performed the experiments.CXS, SL,CYZ and GPL analyzed the data. XYY, DDH and ADC processed and typeset the figures. SL, CYZ and QWW wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Qiwen Wu or Aidong Chen.

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The guidelines outlined in the Declaration of Helsinki were followed when collecting clinical samples. The Nanjing Medical University Institutional Review Board authorized protocols that adhered to standards for the safety of human participants. Each study participant gave written informed consent for sample collection and analysis. Mice were raised and used in particular pathogen-free environments following Nanjing Medical University-approved guidelines. The National Institutes of Health Guide for the Care and Use of Laboratory Animals was followed in all animal experimentation.

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Zhang, X., Hu, D., Sun, X. et al. PHGDH/SYK: a hub integrating anti-fungal immunity and serine metabolism. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01374-7

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