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Malonate promotes CD8+ T cell memory formation via protein malonylation

Cellular & Molecular Immunology volume 22, pages 674–689 (2025)Cite this article

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Abstract

Protein malonylation represents a recently identified posttranslational modification whose role in CD8+ T cell differentiation and functionality remains incompletely understood. In this study, we demonstrate that enhancing protein malonylation through sodium malonate (SM) treatment promotes CD8+ T cell memory formation in response to bacterial infection, subsequently potentiating recall responses. Comparative metabolomic analysis between SM-treated and control CD8+ T cells revealed significant metabolic alterations associated with protein malonylation. We present the first comprehensive proteomic analysis of lysine malonylation in murine CD8+ T cells, identifying 77 malonylation sites across 64 proteins involved in diverse cellular processes, particularly metabolic pathways. Malonylation of STAT6 was confirmed via the use of a specific chemical probe. Notably, we established that malonylation at the lysine 374 site of STAT6 results in increased TCF1 expression, due to alleviated transcriptional repression of TCF1 by STAT6. Collectively, our findings provide compelling evidence that protein malonylation plays a significant role in regulating CD8+ T cell memory formation.

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Data availability

This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the Lead Contact upon request.

Code availability

This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the Lead Contact upon request.

Materials availability

All unique/stable reagents generated in this study are available from the Lead Contact with a completed Materials Transfer Agreement.

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Acknowledgements

We thank Professor Baojun Zhang for his valuable suggestions for this study. This work was supported in part by the National Key R&D Program of China (2022YFA0807300), the National Natural Science Foundation of China (82350114, 82271775 to LZ; 82373073 to YL; 82101829 to QD), the Natural Science Foundation Outstanding Youth Fund of Jiangsu Province (BK20220049), and the CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-047, CIFMS 2021-I2M-1-061, 2023-I2M-2-010 and 2024-I2M-TS-033). We thank the Suzhou Municipal Key Laboratory (SZS2023005) and the NCTIB Fund for R&D Platform for Cell and Gene Therapy.

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Author notes

  1. These authors contributed equally: Qianqian Duan, Jiajia Wang, Liang Sun.

  2. These authors jointly supervised this work: Aijun Zhang, Yong Liu, Lianjun Zhang.

Authors and Affiliations

  1. National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu, 215123, China

    Qianqian Duan, Jiajia Wang, Wenhui Li, Xiaowei Liu & Lianjun Zhang

  2. Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, Jiangsu, 215123, China

    Qianqian Duan, Jiajia Wang, Wenhui Li, Xiaowei Liu & Lianjun Zhang

  3. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China

    Qianqian Duan

  4. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China

    Liang Sun, Zihan Chen & Yong Liu

  5. Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China

    Aijun Zhang

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  1. Qianqian Duan
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Contributions

QD, JW, LS, and ZC performed most of the experiments. QD and LZ wrote the manuscript. JW and XL maintained the mouse line and genotyping. WL provided guidance and assisted with the immunofluorescence and metabolic experiments. AZ and YL provided critical reagents and valuable suggestions. AZ, YL, and LZ revised the manuscript. LZ designed and supervised the project. All the authors read the manuscript and approved the submitted version.

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Correspondence to Aijun Zhang, Yong Liu or Lianjun Zhang.

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Duan, Q., Wang, J., Sun, L. et al. Malonate promotes CD8+ T cell memory formation via protein malonylation. Cell Mol Immunol 22, 674–689 (2025). https://doi.org/10.1038/s41423-025-01294-7

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