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NKG2D is a transmembrane protein belonging to the CD94/NKG2 family of C-type lectin-like receptors.[1] NKG2D is encoded by KLRK1 gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice[2] and chromosome 12 in humans.[3] In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages.[4] In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells.[5] NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.[6]


Human NKG2D receptor complex assembles into a hexameric structure. NKG2D itself forms a homodimer whose ectodomains serve for ligand binding.[7] Each NKG2D monomer is associated with DAP10 dimer. This association is maintained by ionic interaction of a positively charged arginine present in a transmembrane segment of NKG2D and negatively charged aspartic acids within both transmembrane regions of DAP10 dimer.[8] DAP10 functions as an adaptor protein and transduces the signal after the ligand binding by recruiting the p85 subunit of PI3K and Grb2-Vav1 complex which are responsible for subsequent downstream events.[9]

In mice, alternative splicing generates two distinct NKG2D isoforms: the long one (NKG2D-L) and the short one (NKG2D-S). NKG2D-L binds DAP10 similarly to human NKG2D. By contrast, NKG2D-S associates with two adaptor proteins: DAP10 and DAP12.[10] DAP10 recruits the p85 subunit of PI3K and a complex of Grb2 and Vav1.[9] DAP12 bears ITAM motif and activates protein tyrosine kinases Syk and Zap70 signalling.[11]

NKG2D ligands

NKG2D ligands are induced-self proteins which are completely absent or present only at low levels on surface of normal cells, but they are overexpressed by infected, transformed, senescent and stressed cells. Their expression is regulated at different stages (transcription, mRNA and protein stabilization, cleavage from the cell surface) by various stress pathways.[12] Among them, one of the most prominent stress pathways is DNA damage response. Genotoxic stress, stalled DNA replication, poorly regulated cell proliferation in tumorigenesis, viral replication or some viral products activate the ATM and ATR kinases. These kinases initiate the DNA damage response pathway which participates in NKG2D ligand upregulation. DNA damage response thus participate in alerting the immune system to the presence of potentially dangerous cells.[13]

All NKG2D ligands are homologous to MHC class I molecules and are divided into two families: MIC and RAET1/ULBP.

MIC family

Human MIC genes are located within the MHC locus and are composed of seven members (MICA-G), of which only MICA and MICB produce functional transcripts. In mice, MIC genes are absent.[14]

RAET1/ULBP family

Among ten known human RAET1/ULBP genes, six encode functional proteins: RAET1E/ULBP4, RAET1G/ULBP5, RAET1H/ULBP2, RAET1/ULBP1, RAET1L/ULBP6, RAET1N/ULBP3. In mice, proteins from orthologous RAET1/ULBP family fall into three subfamiles: Rae-1, H60, and MULT-1.[14]


NKG2D is a major recognition receptor for the detection and elimination of transformed and infected cells as its ligands are induced during cellular stress, either as a result of infection or genomic stress such as in cancer.[15] In NK cells, NKG2D serves as an activating receptor, which itself is able to trigger cytotoxicity. The function of NKG2D on CD8+ T cells is to send co-stimulatory signals to activate them.[16]

Role in viral infection

Viruses, as intracellular pathogens, can induce the expression of stress ligands for NKG2D. NKG2D is thought to be important in viral control as viruses have adapted mechanisms by which to evade NKG2D responses.[17] For example, cytomegalovirus (CMV) encodes a protein, UL16, which binds to NKG2D ligands ULBP1 and 2 (thus their name "UL16-binding protein") and MICB, which prevents their surface expression.[18]

Role in tumour control

As cancerous cells are "stressed", NKG2D ligands become upregulated, rendering the cell susceptible to NK cell-mediated lysis. Tumor cells that can evade NKG2D responses are thus more likely to propagate.[17][19]

Role in senescent cell removal

As part of the DNA damage response during induction of cellular senescence, cells upregulate the expression of NKG2D ligands that enable NK-mediated killing of senescent cells via the granule exocytosis pathway. [20][21]


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