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Distinct palmitoylation of Foxp3 regulates the function of regulatory T cells via palmitoyltransferases

Cellular & Molecular Immunology (2024)Cite this article

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Regulatory T cells (Tregs) play pivotal roles in maintaining immune homeostasis and preventing excessive immune responses in vivo. As key players in suppressing immune reactions, they help to preserve immune tolerance and are thus crucial for preventing autoimmune diseases. Within the tumor microenvironment (TME), Tregs facilitate tumor immune evasion by impairing the activity of effector cells via multiple mechanisms, thus contributing to the initiation and progression of tumors [1]. To perform this regulatory function, Tregs depend on the master transcription factor forkhead box protein p3 (Foxp3) [2]. The expression of Foxp3 has emerged as indispensable for the development and optimal function of Tregs [3]. Interestingly, different posttranslational modifications, including phosphorylation, ubiquitination, glycosylation, and acetylation, exert significant regulatory effects on the biological function of Foxp3 [4,5,6,7,8].

Palmitoylation is a reversible lipid posttranslational modification characterized by the addition of a 16-carbon palmitoyl group to a cysteine residue via a thioester bond. This modification is crucial for modulating various characteristics of proteins, including their subcellular localization, protein‒protein interactions, stability, and signal transduction activity [9,10,11]. Recent studies have elucidated key players in the palmitoylation process. Notably, a family of 24 mammalian palmitoyltransferases, known as Asp-His-His-Cys (DHHC) motif-containing proteins, has attracted considerable interest. These enzymes are responsible for catalyzing the addition of the palmitoyl group to a target protein. Additionally, the identification of multiple depalmitoylating enzymes, such as APT1/2, PPT1/2, and ABHD17a/b/c, has revealed the roles of these enzymes in removing palmitoyl groups. The dynamic balance between palmitoylation and depalmitoylation is essential for modulating protein function and coordinating cellular signaling. However, whether the function of Foxp3 is regulated by its palmitoylation under physiological  conditions and in the TME is unknown. Therefore, our study aimed to detect palmitoylated Foxp3 and to determine the effects of Foxp3 palmitoylation on antitumor immune responses.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant no. 32000491 to BHZ), projects 222300420015 and 2023DK2005 to YML, and a start-up fund from Xinxiang Medical University (505483, to BHZ).

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  1. These authors contributed equally: Binhui Zhou, Mengjie Zhang, Haoyuan Ma, Ying Wang.

Authors and Affiliations

  1. Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, China

    Binhui Zhou, Ying Wang & Eryan Kong

  2. Laboratory of Mouse Genetics, Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 453003, China

    Binhui Zhou, Ying Wang, Eryan Kong & Yinming Liang

  3. Laboratory of Genetic Regulators in the Immune System, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, China

    Binhui Zhou, Mengjie Zhang, Haoyuan Ma, Juanjuan Qiu, Yang Liu, Liaoxun Lu, Lichen Zhang, Rong Huang, Yanrong Gu & Yinming Liang

  4. Basic Medical College, Xinxiang Medical University, Xinxiang, 453003, China

    Tianhan Li

  5. Center of Disease Model and Immunology, Hunan Academy of Chinese Medicine, Changsha, China

    Yinming Liang

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  1. Binhui Zhou
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Contributions

BZ, EK, and YL designed the experiments. BZ, MZ, HM, YW, JQ, and YL performed the experiments and collected the data. LL, TL, LZ, YG, and RH assisted in the experiments. BZ analyzed the data and wrote the original manuscript. YL revised the manuscript.

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Correspondence to Binhui Zhou, Eryan Kong or Yinming Liang.

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The authors declare no competing interests.

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Zhou, B., Zhang, M., Ma, H. et al. Distinct palmitoylation of Foxp3 regulates the function of regulatory T cells via palmitoyltransferases. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01166-6

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