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zDHHC20-driven S-palmitoylation of CD80 is required for its costimulatory function

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

CD80 is a transmembrane glycoprotein belonging to the B7 family, which has emerged as a crucial molecule in T cell modulation via the CD28 or CTLA4 axes. CD80-involved regulation of immune balance is a finely tuned process and it is important to elucidate the underlying mechanism for regulating CD80 function. In this study we investigated the post-translational modification of CD80 and its biological relevance. By using a metabolic labeling strategy, we found that CD80 was S-palmitoylated on multiple cysteine residues (Cys261/262/266/271) in both the transmembrane and the cytoplasmic regions. We further identified zDHHC20 as a bona fide palmitoyl-transferase determining the S-palmitoylation level of CD80. We demonstrated that S-palmitoylation protected CD80 protein from ubiquitination degradation, regulating the protein stability, and ensured its accurate plasma membrane localization. The palmitoylation-deficient mutant (4CS) CD80 disrupted these functions, ultimately resulting in the loss of its costimulatory function upon T cell activation. Taken together, our results describe a new post-translational modification of CD80 by S-palmitoylation as a novel mechanism for the regulation of CD80 upon T cell activation.

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Fig. 1: CD80 is S-palmitoylated on multiple cysteine residues.
Fig. 2: zDHHC20 is a major palmitoyl-transferase catalyzing CD80 S-palmitoylation.
Fig. 3: The S-palmitoylation of CD80 is required for its protein stability.
Fig. 4: S-palmitoylation facilitates an accurate plasma membrane localization and maintains costimulatory function for CD80.

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Acknowledgements

This work was supported by grants from Zhejiang Provincial Natural Science Foundation of China (LR22H310002 to JC), the National Natural Science Foundation of China (No. 82330114 to QH), and the Fundamental Research Funds for the Central Universities (226-2023-00059).

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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310000, China

    Bin Lu, Yi-yun Sun, Bo-ya Chen, Bo Yang, Qiao-jun He & Ji Cao

  2. Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou, 310000, China

    Bo Yang, Qiao-jun He & Ji Cao

  3. Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, 310000, China

    Bo Yang, Qiao-jun He, Jun Li & Ji Cao

  4. The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310000, China

    Bo Yang, Qiao-jun He & Ji Cao

  5. School of Medicine, Hangzhou City University, Hangzhou, 310000, China

    Bo Yang

  6. Cancer Center of Zhejiang University, Hangzhou, 310000, China

    Qiao-jun He, Jun Li & Ji Cao

  7. Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China

    Jun Li

  8. Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou, 310000, China

    Jun Li

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Contributions

Conception and design: BL, BY, QJH, JL and JC; Experimental operation: BL, YYS and BYC; Collection and assembly of data: BL; Manuscript writing: BL and JC; Final approval of manuscript: all authors.

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Correspondence to Qiao-jun He, Jun Li or Ji Cao.

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Lu, B., Sun, Yy., Chen, By. et al. zDHHC20-driven S-palmitoylation of CD80 is required for its costimulatory function. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01248-1

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