Purine nucleotide metabolism regulates expression of the human immune ligand MICA

Abstract

Running titlePurine nucleotide metabolism regulates MICA expression Keywords Immunology, Warburg effect, Purine, Natural killer cells (NK cells), Metabolism, NKG2D ligands, Purine metabolism, Glucose metabolism, Immunometabolism, Immunosurveillance Abstract Expression of the cell surface glycoprotein MHC class I polypeptide-related sequence A (MICA) is induced in dangerous, abnormal or 'stressed' cells, including cancer cells, virus-infected cells and rapidly proliferating cells. MICA is recognized by the activating immune cell receptor NKG2D, providing a mechanism by which immune cells can identify and potentially eliminate pathological cells. Immune recognition through NKG2D is implicated in cancer, atherosclerosis, transplant rejection and inflammatory diseases such as rheumatoid arthritis. Despite the wide range of potential therapeutic applications of MICA manipulation, the factors that control MICA expression are unclear. Here we use metabolic interventions and metabolomic analyses to show that the transition from quiescent cellular metabolism to a 'Warburg' or biosynthetic metabolic state induces MICA expression. Specifically, we show that glucose transport into the cell and active glycolytic metabolism are necessary to upregulate MICA expression. Active purine synthesis is necessary to support this effect of glucose, and increases in purine nucleotide levels are sufficient to induce MICA expression.Metabolic induction of MICA expression directly influences NKG2D-dependent cytotoxicity by immune cells. These findings support a model of MICA regulation whereby the purine metabolic activity of individual cells is reflected by cell surface MICA expression and is the subject of surveillance by NKG2D receptor-expressing immune cells.

Inosine pranobex enhances human NK cell cytotoxicity by inducing metabolic activation and NKG2D ligand expression

“…1F). This is similar to the pattern of NKG2DL expression we have previously reported in response to a shift to Warburg metabolism with increased purine nucleotide levels [16].…”

Cytoplasmic Citrate Flux Modulates the Immune Stimulatory NKG2D Ligand MICA in Cancer Cells

“…Recently, it was shown that purine biosynthesis was critical for glucose-induced MICA expression (16). We therefore tested if MICA expression in MGAT5 KO cells was caused by enhanced purine biosynthesis, but MICA expression in MGAT5 KO cells was unaffected by the purine biosynthesis inhibitor 6-mercaptopurine (6-MP) and even slightly increased by the inhibitor azaserine (Supplementary Figures S3C,D).…”

“…Expression of NKG2DLs is associated with hyperproliferation (8) and thus with highly active metabolism. Two studies have linked NKG2DL expression to active glycolysis (15,16), whereas one study reports that inhibition of glycolysis increased basal NKG2DL expression in breast cancer cell lines (17,18). These studies emphasize a link to proliferative cell metabolism, and suggest that the role of glycolysis in NKG2DL regulation is context-specific.…”

Tumor Microenvironment-Induced Immunometabolic Reprogramming of Natural Killer Cells

“…Though direct studies on the effects of purine metabolism, particularly that of adenosine, on the functions and phenotypes of NK cells are limited, insights are starting to emerge. McCarthy et al ( 108 ) observed that the generation of purine nucleotides, including adenosine, through glycolysis drives the expression of MICA ligands on cells, which are then targeted by NKG2D receptors on NK cells. Restricting early glycolytic pathway intermediates abrogated the expression of MICA, showing that cell proliferation was not shown to be a prerequisite for MICA expression.…”