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

Møller, Sofie Hedlund; Mellergaard, Maiken; Madsen, Mikkel; Bermejo, Amaia Vergara; Jepsen, Stine Dam; Hansen, Marie Haugsten; Høgh, Rikke Illum; Aldana, Blanca I.; Desler, Claus; Rasmussen, Lene Juel; Sustarsic, Elahu G.; Gerhart-Hines, Zachary; Daskalaki, Evangelia; Wheelock, Craig E.; Hiron, Thomas K.; Lin, Dazhen; O’Callaghan, Christopher A.; Wandall, Hans H.; Andresen, Lars Ole; Skov, Søren

doi:10.3389/fimmu.2020.01968

Cited by 12 publications

(5 citation statements)

References 97 publications

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“…As energetic output is often associated with increased cell division, some studies have determined that nutrient availability influences ligand expression. For example, enhanced mitochondrial citrate metabolism, glycolysis, and fatty acid metabolism promoted either ligand expression (MICA/B) or enhanced NK cell functionality in their respective tumor models, which supports the potential targeting of metabolically active cell populations [129][130][131][132].…”

Section: Cell Cycle Alterationsmentioning

confidence: 70%

Regulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression

Friedman

2022

Cancers

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Under cellular distress, multiple facets of normal homeostatic signaling are altered or disrupted. In the context of the immune landscape, external and internal stressors normally promote the expression of natural killer group 2 member D (NKG2D) ligands that allow for the targeted recognition and killing of cells by NKG2D receptor-bearing effector populations. The presence or absence of NKG2D ligands can heavily influence disease progression and impact the accessibility of immunotherapy options. In cancer, tumor cells are known to have distinct regulatory mechanisms for NKG2D ligands that are directly associated with tumor progression and maintenance. Therefore, understanding the regulation of NKG2D ligands in cancer will allow for targeted therapeutic endeavors aimed at exploiting the stress response pathway. In this review, we summarize the current understanding of regulatory mechanisms controlling the induction and repression of NKG2D ligands in cancer. Additionally, we highlight current therapeutic endeavors targeting NKG2D ligand expression and offer our perspective on considerations to further enhance the field of NKG2D ligand biology.

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Section: Cell Cycle Alterationsmentioning

confidence: 70%

Regulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression

Friedman

2022

Cancers

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“…Metabolic rewiring is another distinctive feature of cancer [ 71 ]. Once again, NKG2DL expression is influenced by cancer-associated metabolic factors such as altered glycosylation [ 69 , 70 ].…”

Section: Induction and Regulation Of Nkg2dl Expression In Cancermentioning

confidence: 99%

The Role and Regulation of the NKG2D/NKG2D Ligand System in Cancer

Tan

Spillane

Maher

2023

Biology

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The family of human NKG2D ligands (NKG2DL) consists of eight stress-induced molecules. Over 80% of human cancers express these ligands on the surface of tumour cells and/or associated stromal elements. In mice, NKG2D deficiency increases susceptibility to some types of cancer, implicating this system in immune surveillance for malignancy. However, NKG2DL can also be shed, released via exosomes and trapped intracellularly, leading to immunosuppressive effects. Moreover, NKG2D can enhance chronic inflammatory processes which themselves can increase cancer risk and progression. Indeed, tumours commonly deploy a range of countermeasures that can neutralise or even corrupt this surveillance system, tipping the balance away from immune control towards tumour progression. Consequently, the prognostic impact of NKG2DL expression in human cancer is variable. In this review, we consider the underlying biology and regulation of the NKG2D/NKG2DL system and its expression and role in a range of cancer types. We also consider the opportunities for pharmacological modulation of NKG2DL expression while cautioning that such interventions need to be carefully calibrated according to the biology of the specific cancer type.

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“…MHC class I chain-related proteins A (MICA) is a Natural Killer Group 2D (NKG2D) ligand, which can facilitate immune surveillance of cancer cells. And N-acetylglucosaminyltransferase V (GnT-V or MGAT5), an N-glycosylation gene, can induce continuous high MICA surface expression [95], which has a high expression in NK cells during missed abortion (Figure 5B), suggesting that GnT-V or MGAT5 may affect the recognition ability and cytotoxicity of dNK cells through the combination of MICA and NKG2D during embryo implantation. Besides, the α -chain of HLA-I molecules undergoes N-glycosylation modification [96] and a single N-glycosylation site is present in HLA-G, potentially augmenting its interaction with NKG2 receptors [97].…”

Section: Protein Glycosylation and Embryo Implantationmentioning

confidence: 99%

Protein glycosylation: bridging maternal–fetal crosstalk during embryo implantation

Sun,

Feng,

et al. 2023

Biology of Reproduction

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Infertility is a challenging health problem that affects 8% to 15% of couples worldwide. Establishing pregnancy requires successful embryo implantation, but about 85% of unsuccessful pregnancies are due to embryo implantation failure or loss soon after. Factors crucial for successful implantation include invasive blastocysts, receptive endometrium, invasion of trophoblast cells, and regulation of immune tolerance in the maternal-fetal interface. Maternal-fetal crosstalk, which relies heavily on protein–protein interactions, is a critical factor in implantation that involves multiple cellular communication and molecular pathways. Glycosylation, a protein modification process, is closely related to cell growth, adhesion, transport, signal transduction, and recognition. Protein glycosylation plays a crucial role in maternal-fetal crosstalk and can be divided into N-glycosylation and O-glycosylation, which are often terminated by sialylation or fucosylation. This review article examines the role of protein glycosylation in maternal-fetal crosstalk based on two transcriptome data from the GEO database (GSE139087 and GSE113790) and existing research, particularly in the context of the mechanism of protein glycosylation and embryo implantation. Dysregulation of protein glycosylation can lead to adverse pregnancy outcomes, such as missed abortion and recurrent spontaneous abortion (RSA), underscoring the importance of a thorough understanding of protein glycosylation in the diagnosis and treatment of female reproductive disorders. This knowledge could have significant clinical implications, leading to the development of more effective diagnostic and therapeutic approaches for these conditions.

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

Cited by 12 publications

References 97 publications

Regulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression

Regulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression

The Role and Regulation of the NKG2D/NKG2D Ligand System in Cancer

Protein glycosylation: bridging maternal–fetal crosstalk during embryo implantation

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