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 natural killer group 2D (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 up-regulate 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.
Highlights
Expression of the cell-surface glycoprotein major histocompatibility complex (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
MHC class I polypeptide-related sequence A (MICA)-expressing cells are targeted by immune cells (including natural killer (NK) cells, NKT cells, and cytotoxic CD8ϩ T cells) that express the activating natural killer group 2D (NKG2D) receptor; this interaction can result in direct cytotoxicity [12], co-stimulation [6, 13, 14], or cytokine secretion [15], depending on the context
We demonstrate that MICA induction by highenergy purine nucleotides is associated with increased NKG2D-dependent cellular immunogenicity and susceptibility to NK cell cytotoxicity, supporting our hypothesis that NKG2D provides a mechanism for immune oversight of metabolically activated cells
Summary
Multiple factors have been associated with changes in MICA expression, including activation of the DNA damage response pathway [19], Toll-like receptor (TLR) stimulation [10], histone deacetylation [20], heat shock transformation [21], ionizing radiation [22], growth factor pathway activation [23], cell-surface shedding [24], and microRNA expression [25]. MICA expression in human primary cells or tissue samples is found in settings independently associated with high metabolic activity (increased glucose uptake, glycolysis, high lactate output, and proportionate reduction in TCA cycle metabolism, or “Warburg metabolism” [27,28,29,30,31]). This state of “activated metabolism” can be considered as a biosynthetic state, where enhanced glycolytic flux generates intermediate substrates for biomolecule synthesis [32]. We demonstrate that MICA induction by highenergy purine nucleotides is associated with increased NKG2D-dependent cellular immunogenicity and susceptibility to NK cell cytotoxicity, supporting our hypothesis that NKG2D provides a mechanism for immune oversight of metabolically activated cells
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