Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response

doi:10.1016/j.cell.2025.01.043

. 2025 Feb 27:S0092-8674(25)00145-X.

doi: 10.1016/j.cell.2025.01.043. Online ahead of print.

Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response

Xiadi He¹, Qiwei Wang², Xin Cheng³, Weihua Wang⁴, Yutong Li³, Yabing Nan³, Jiang Wu⁵, Bingqiu Xiu⁴, Tao Jiang⁴, Johann S Bergholz², Hao Gu³, Fuhui Chen⁶, Guangjian Fan⁷, Lianhui Sun⁸, Shaozhen Xie⁴, Junjie Zou⁹, Sheng Lin⁹, Yun Wei¹⁰, James Lee⁴, John M Asara¹¹, Ke Zhang¹², Lewis C Cantley⁶, Jean J Zhao¹³

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Center for Metabolic Diseases (Shanghai), Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Lifecycle Health Management Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
⁶ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
⁷ Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
⁸ Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiao Tong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China.
⁹ XtalPi Technology Co., Ltd., Shanghai 200131, China.
¹⁰ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
¹¹ Division of Signal Transduction/Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
¹³ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jean_zhao@dfci.harvard.edu.

PMID: 40023152
DOI: 10.1016/j.cell.2025.01.043

Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response

Xiadi He et al. Cell. 2025.

. 2025 Feb 27:S0092-8674(25)00145-X.

doi: 10.1016/j.cell.2025.01.043. Online ahead of print.

Authors

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Center for Metabolic Diseases (Shanghai), Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Lifecycle Health Management Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
⁶ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
⁷ Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
⁸ Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiao Tong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China.
⁹ XtalPi Technology Co., Ltd., Shanghai 200131, China.
¹⁰ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
¹¹ Division of Signal Transduction/Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
¹³ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jean_zhao@dfci.harvard.edu.

PMID: 40023152
DOI: 10.1016/j.cell.2025.01.043

Abstract

Vitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanisms remain elusive. Here, we report that vitC directly modifies lysine residues to form "vitcyl-lysine"-a process termed vitcylation. Vitcylation occurs in a dose-, pH-, and sequence-dependent manner in both cell-free systems and living cells. Mechanistically, vitC vitcylates signal transducer and activator of transcription-1 (STAT1)- lysine-298 (K298), impairing its interaction with T cell protein-tyrosine phosphatase (TCPTP) and preventing STAT1-Y701 dephosphorylation. This leads to enhanced STAT1-mediated interferon (IFN) signaling in tumor cells, increased major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class I expression, and activation of anti-tumor immunity in vitro and in vivo. The discovery of vitcylation as a distinctive post-translational modification provides significant insights into vitC's cellular function and therapeutic potential, opening avenues for understanding its biological effects and applications in disease treatment.

Keywords: STAT1; immune response; protein modification; vitamin C; vitcylation.

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Conflict of interest statement

Declaration of interests Q.W. is a scientific consultant for Crimson Biopharm Inc. J.S.B. is a scientific consultant for Geode Therapeutics Inc. L.C.C. is a co-founder and scientific advisory board member of Agios Pharmaceuticals, Faeth Therapeutics, Petra Pharma Corporation, Larkspur Therapeutics, and Volastra Pharmaceuticals and a scientific advisory board member for Scorpion Therapeutics. J.J.Z. is co-founder and director of Crimson Biopharm Inc. and Geode Therapeutics Inc.

Update of

Lysine vitcylation is a novel vitamin C-derived protein modification that enhances STAT1-mediated immune response.
He X, Wei Y, Wu J, Wang Q, Bergholz JS, Gu H, Zou J, Lin S, Wang W, Xie S, Jiang T, Lee J, Asara JM, Zhang K, Cantley LC, Zhao JJ. He X, et al. bioRxiv [Preprint]. 2023 Jun 27:2023.06.27.546774. doi: 10.1101/2023.06.27.546774. bioRxiv. 2023. Update in: Cell. 2025 Feb 27:S0092-8674(25)00145-X. doi: 10.1016/j.cell.2025.01.043. PMID: 37425798 Free PMC article. Updated. Preprint.

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Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response

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Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response

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Abstract

Conflict of interest statement

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Abstract

Conflict of interest statement

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