Innate immune activating ligand SUMOylation affects tumor cell recognition by NK cells
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Updated: Feb 23, 2026
SUMO-Binding Entities SUBEs as Tools for the Enrichment, Isolation, Identification, and Characterization of the SUMO Proteome in Liver Cancer
Published on: November 1, 2019
Beatrice Zitti1, Rosa Molfetta2, Cinzia Fionda1
1Department of Molecular Medicine, "Sapienza" University of Rome, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, "Viale Regina Elena 291, 00161, Rome, Italy.
Abstract:
Natural Killer cells are innate lymphocytes involved in tumor immunosurveillance. They express activating receptors able to recognize self-molecules poorly expressed on healthy cells but up-regulated upon stress conditions, including transformation. Regulation of ligand expression in tumor cells mainly relays on transcriptional mechanisms, while the involvement of ubiquitin or ubiquitin-like modifiers remains largely unexplored. Here, we focused on the SUMO pathway and demonstrated that the ligand of DNAM1 activating receptor, PVR, undergoes SUMOylation in multiple myeloma. Concurrently, we found that PVR is preferentially located in intracellular compartments in human multiple myeloma cell lines and malignant plasma cells and that inhibition of the SUMO pathway promotes its translocation to the cell surface, increasing tumor cell susceptibility to NK cell-mediated cytolysis. Our findings provide the first evidence of an innate immune activating ligand regulated by SUMOylation, and confer to this modification a novel role in impairing recognition and killing of tumor cells.
Insights
SUMOylation of PVR, a ligand for Natural Killer (NK) cell receptor DNAM1, hinders tumor cell recognition. Inhibiting SUMOylation enhances NK cell-mediated killing of multiple myeloma cells.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Natural Killer (NK) cells are crucial for tumor immunosurveillance, recognizing stress-induced ligands on cancer cells.
- While transcriptional regulation of ligand expression is known, the role of post-translational modifications like SUMOylation is largely unexplored.
Purpose of the Study:
- To investigate the role of the SUMOylation pathway in regulating the expression and function of PVR, a DNAM1 receptor ligand, in multiple myeloma.
- To determine if targeting SUMOylation can enhance NK cell-mediated killing of multiple myeloma cells.
Main Methods:
- Analysis of PVR SUMOylation in human multiple myeloma cell lines and patient samples.
- Cellular localization studies of PVR in normal and SUMOylation-inhibited conditions.
- Assessment of NK cell-mediated cytolysis against multiple myeloma cells with and without SUMOylation inhibition.
Main Results:
- PVR undergoes SUMOylation in multiple myeloma cells.
- SUMOylation causes PVR to accumulate in intracellular compartments, reducing its surface expression.
- Inhibition of the SUMOylation pathway promotes PVR translocation to the cell surface, increasing susceptibility to NK cell-mediated killing.
Conclusions:
- SUMOylation represents a novel regulatory mechanism for innate immune activating ligands like PVR.
- This modification impairs tumor cell recognition and killing by NK cells in multiple myeloma.
- Targeting the SUMOylation pathway offers a potential strategy to enhance anti-tumor immunity.
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