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

Bin Lu1, Yi-yun Sun1, Bo-ya Chen1, Bo Yang1,2,3,4,5, Qiao-jun He1,2,3,4,6, Jun Li3,6,7,8, Ji Cao1,2,3,4,6
1 Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China
2 Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou 310000, China
3 Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou 310000, China
4 The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310000, China
5 School of Medicine, Hangzhou City University, Hangzhou 310000, China
6 Cancer Center of Zhejiang University, Hangzhou 310000, China
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
8 Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou 310000, China
Correspondence to: Qiao-jun He:, Jun Li:, Ji Cao:,
DOI: 10.1038/s41401-024-01248-1
Received: 24 October 2023
Accepted: 21 February 2024
Advance online: 11 March 2024


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.

Keywords: CD80; zDHHC20; S-palmitoylation; costimulatory signals; T cell activation

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