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MYO1F regulates T-cell activation and glycolytic metabolism by promoting the acetylation of GAPDH

Cellular & Molecular Immunology volume 22, pages 176–190 (2025)Cite this article

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Abstract

Proper cellular metabolism in T cells is critical for a productive immune response. However, when dysregulated by intrinsic or extrinsic metabolic factors, T cells may contribute to a wide spectrum of diseases, such as cancers and autoimmune diseases. However, the metabolic regulation of T cells remains incompletely understood. Here, we show that MYO1F is required for human and mouse T-cell activation after TCR stimulation and that T-cell-specific Myo1f knockout mice exhibit an increased tumor burden and attenuated EAE severity due to impaired T-cell activation in vivo. Mechanistically, after TCR stimulation, MYO1F is phosphorylated by LCK at tyrosines 607 and 634, which is critical for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) acetylation at Lys84, 86 and 227 mediated by α-TAT1, which is an acetyltransferase, and these processes are important for its activation, cellular glycolysis and thus the effector function of T cells. Importantly, we show that a fusion protein of VAV1-MYO1F, a recurrent peripheral T-cell lymphoma (PTCL)-associated oncogenic protein, promotes hyperacetylation of GAPDH and its activation, which leads to aberrant glycolysis and T-cell proliferation, and that inhibition of the activity of GAPDH significantly limits T-cell activation and proliferation and extends the survival of hVAV1-MYO1F knock-in mice. Moreover, hyperacetylation of GAPDH was confirmed in human PTCL patient samples containing the VAV1-MYO1F gene fusion. Overall, this study revealed not only the mechanisms by which MYO1F regulates T-cell metabolism and VAV1-MYO1F fusion-induced PTCL but also promising therapeutic targets for the treatment of PTCL.

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Acknowledgements

This investigation was supported by grants from the National Science Fund for Distinguished Young Scholars (82225029, to C.H.W.); the Youth Fund of the National Natural Science Foundation of China (82302628, to Y.Y.D., 82301989, to R.R.H., 82301987 to B.Z. and 82402704 to Y.Y.L.); the Original Exploration Program of the National Natural Science Foundation of China (82150102, to C.H.W.); the National Key Research and Development Program of China (2020YFA0710700, to C.H.W.); the Postdoctoral Foundation of China (2022M720658, to Y.Y.D., and 2022M720659 to R.R.H.); the Sichuan Postdoctoral Innovation Plan (BX202202, to Y.Y.D.); the Postdoctoral Foundation of Sichuan Provincial People’s Hospital (2022BH01, to R.R.H. and 2022BH07, to M.Y.); and the Postdoctoral Foundation of Sichuan Province (TB2022086, to R.R.H., TB2023092, to L.Y.F.).

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  1. These authors contributed equally: Zhihui Cui, Heping Wang.

Authors and Affiliations

  1. Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074; Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Zhihui Cui, Heping Wang, Xiong Feng & Ru Gao

  2. The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Chuyu Wu, Ming Yi, Ruirui He, Lingyun Feng, Bo Zeng, Yanyun Du & Chenhui Wang

  3. Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China

    Chuyu Wu, Ming Yi, Ruirui He, Lingyun Feng, Bo Zeng, Yanyun Du & Chenhui Wang

  4. Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People’s Hospital, Chengdu, China

    Chuyu Wu, Ming Yi, Ruirui He, Lingyun Feng, Bo Zeng, Yanyun Du & Chenhui Wang

  5. School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China

    Chuyu Wu, Ming Yi, Ruirui He, Ting Pan, Lingyun Feng, Bo Zeng, Guoling Huang, Yuan Wang, Yanyun Du, Cun-jin Zhang & Chenhui Wang

  6. Department of Neurology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Cun-jin Zhang

  7. Department of Pathology, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China

    Xue Xiao

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  1. Zhihui Cui
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Contributions

ZHC and HPW performed the experiments with the assistance of XF, YYD, MY, RRH, TP, RG, LYF, BZ, GLH, and YW; CYW, and CJZ helped to perform the EAE experiments; XX helped to obtain the human PTCL samples and scored the acetylation level of GAPDH in the samples. ZHC and CHW designed the experiments and analyzed the data; CHW wrote the manuscript and supervised the project with YYD, CJZ, and XX.

Corresponding authors

Correspondence to Yanyun Du, Cun-jin Zhang, Xue Xiao or Chenhui Wang.

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Cui, Z., Wang, H., Feng, X. et al. MYO1F regulates T-cell activation and glycolytic metabolism by promoting the acetylation of GAPDH. Cell Mol Immunol 22, 176–190 (2025). https://doi.org/10.1038/s41423-024-01247-6

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