Lysine Vitcylation: A Novel Vitamin C-Induced Modification Enhancing Immune Response

Vitamin C (vitC) is widely recognized for its essential role in human health, with increasing evidence suggesting its therapeutic potential in diseases like cancer. However, the precise mechanisms underlying its biological effects have remained unclear. A groundbreaking study now reveals that vitamin C chemically modifies lysine residues in proteins, a process termed lysine vitcylation. This newly identified post-translational modification has significant implications for immune regulation and potential clinical applications.

Discovery of Lysine Vitcylation

The study demonstrates that vitamin C directly interacts with lysine residues in proteins, forming a novel modification called vitcyl-lysine. This vitcylation process occurs in a dose-dependent, pH-sensitive, and sequence-specific manner, affecting proteins in both isolated systems and living cells. The modification provides a new perspective on how vitamin C can regulate cellular functions beyond its traditional roles in collagen synthesis and antioxidant activity.

Enhancing STAT1-Mediated Immune Response

One of the most striking findings of the study is that lysine vitcylation specifically modifies lysine-298 (K298) on the STAT1 protein, a key regulator of immune signaling. This modification disrupts STAT1’s interaction with T cell protein-tyrosine phosphatase (TCPTP), preventing the dephosphorylation of tyrosine-701 (Y701). As a result, STAT1 remains in an active phosphorylated state, leading to:

Stronger Interferon (IFN) signaling: Enhanced immune response activation.

Increased expression of MHC/HLA class I molecules: Boosting immune recognition of tumor cells.

Improved anti-tumor immunity: Both in laboratory experiments and animal models.

These findings suggest that vitamin C, through vitcylation, can significantly enhance immune system function and potentially improve cancer immunotherapy outcomes.

Implications for Therapeutic Applications

The discovery of lysine vitcylation opens up new possibilities for understanding vitamin C’s biological effects and clinical applications. Potential implications include:

Cancer Treatment: By boosting interferon signaling and enhancing immune surveillance, vitamin C could improve responses to immunotherapies.

Autoimmune and Inflammatory Diseases: Modulating STAT1 activity might help fine-tune immune responses in various conditions.

Drug Development: Targeting vitcylation pathways could lead to novel therapeutic strategies.

Conclusion

Lysine vitcylation represents a previously unrecognized mechanism by which vitamin C influences immune signaling and cellular function. This discovery not only deepens our understanding of vitamin C’s role in human health but also offers exciting new avenues for its application in disease treatment, particularly in cancer immunotherapy. As research progresses, harnessing vitcylation may unlock novel therapeutic strategies for enhancing immune responses against diseases.

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00145-X