NKG2D

Last updated
KLRK1
Protein KLRK1 PDB 1hyr.png
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases KLRK1 , CD314, D12S2489E, KLR, NKG2-D, NKG2D, natural killer group 2D, killer cell lectin-like receptor K1, killer cell lectin like receptor K1
External IDs OMIM: 611817 HomoloGene: 136440 GeneCards: KLRK1
Orthologs
SpeciesHumanMouse
Entrez

22914

n/a

Ensembl

ENSG00000213809

n/a

UniProt

P26718

n/a

RefSeq (mRNA)

NM_007360

n/a

RefSeq (protein)

NP_001186734

n/a

Location (UCSC) Chr 12: 10.37 – 10.39 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors. [3] NKG2D is encoded by KLRK1 (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice [4] and chromosome 12 in humans. [5] In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages. [6] In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells. [7] NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells. [8]

Contents

Structure

Human NKG2D receptor complex assembles into a hexameric structure. NKG2D itself forms a homodimer whose ectodomains serve for ligand binding. [9] 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. [10] 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. [11]

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. [12] DAP10 recruits the p85 subunit of PI3K and a complex of Grb2 and Vav1. [11] DAP12 bears ITAM motif and activates protein tyrosine kinases Syk and Zap70 signalling. [13]

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. [14] 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. [15]

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. [16]

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 subfamilies: Rae-1, H60, and MULT-1. [16] ULBP2 is a stress-induced ligand often found on senescent cells. [17]

NKG2D ligand regulation

NKG2D ligand expression is regulated on multiple levels such as transcriptional, RNA splicing, posttranscriptional and posttranslational. On the transcriptional level, NKG2D ligands can be regulated by transcription factors or regulatory sequences in various molecular pathways. Also, the regulation of NKG2D ligands after cell stress, proliferation signals, infection or oxidative stress is able to activate a DNA damage response (DDR). [18] Ligation of sensor kinases ATM and ATR leads to activation of different checkpoint kinases, such as Chk1 and Chk2, [19] which are important for the induction of MIC, ULBPs or Reat1 genes [15] ). One of the major signals for cell expression of NKG2D is the triggering of DDR along with the induction of senescence program. [15] RNA splicing is another mechanism influencing NKG2D ligand expression. For MICA, [20] ULBP4 [21] and ULBP5, [22] alternative splicing isoforms have been shown. However, the molecular mechanisms of this type of regulation are unknown. In posttranscriptional regulation, stabilization of NKG2D ligand mRNA plays a key role. For example AUF1 protein, which mediates RNA degradation, constitutively targets mRNA of NKG2D ligands. [23] Additionally, surface expression levels of NKG2D can be controlled by soluble forms of various protease-mediated cleavages and exosome expression. [24]

Function

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. [25] 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. [6]

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. [26] 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. [27]

Role in tumor control

As cancerous cells are "stressed", NKG2D ligands become upregulated, rendering the cell susceptible to NK cell-mediated lysis. However, some tumor cells have acquired the capacity to evade this immune surveillance. They have created the capacity of reducing and eliminating the high volume of NKG2DL present on the cell surface of tumor cells by secreting metalloproteases that cleave these ligands, and therefore they escape from the control of NK cells and their cytotoxic activity. TGF-β allows immune surveillance escape by inhibiting T and NK cell function. [28] Tumor cells that can evade NKG2D responses are thus more likely to propagate. [26] [29]

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. [30] [31] Specifically, MICA and ULBP2 proteins on senescent cells are recognized by the NKG2D receptor on Natural Killer cells, which is necessary for efficient recognition and elimination of senescent cells. [30]

Interventions to increase senescent cell surface ligands of the Natural Killer cell receptor NKG2D have been proposed as a senolytic therapy to remove senescent cells. [32]

NKG2D signalling

When NKG2D receptor binds to any of its ligands, an activation cascade starts for activating the respective immune cell. NKG2D does not possess any signaling elements within its intracellular domain. NKG2D forms a homodimer and associates with adaptor proteins in its transmembrane domain to a hexameric complex structure and initiate signaling cascades. [33] In both mice and humans, this signalling depends on the association between NKG2D and DAP10 protein forming a complex. Upon ligand engagement, Tyr-X-X-Meth (YXXM) motif within the cytoplasmic domain of DAP10 recruits PI3K and Grb2 to activate NK cell cytotoxicity pathways. [33] In mice, NKG2D associates with DAP 12, instead of DAP 10, and NKG2D-DAP12 complex is involved in IFN-γ production through the Syk and ZAP70 pathway. [28]

Therefore, NKG2D is implicated in NK and other immune cells activation through the PI3K-AKT pathway. This pathway activation depend on two main basis. The first is the plasticity and structural changes of NKG2D (receptor) when binding to its ligands. The last one is the association of DAP10 in the intracellular domain of the receptor and the recruitment of PI3K and Grb.

NKG2D and NK cells

NK cells are a key part of innate immunity, mainly involved in the early cytolytic defense against infections and tumors. NK cell activity is mediated by a variety of cell surface receptors with stimulatory and inhibitory activity. Under normal conditions, NK cells exist in an inactive state, with signaling dominated by inhibitory receptor activation.

NKG2G is a key stimulatory cell surface receptor. A low expression of the receptor is observed already in the early NK cells precursor stages, also the concentration of receptors is increased with maturation of NK cells. [34] In mice, both NKG2D isoforms were detected.  During resting state, predominance of long forms of NKG2D is typical, while in activated cells there is a higher number of short forms. [35]

Interaction with IL-15 receptor (IL-15R) is a crucial factor for development, homeostasis and survival of NK cells and NKG2D signaling seems to be similarly critical. [36] Connection between these two pathways is the binding of DAP10, adaptor protein and signal transducer, which associates with IL-15R or NKG2D, respectively. [37] This phenomenon was proven by experiments on mice knocked out in Klrk1 – such mice have higher proliferation rate, faster differentiation and maturation of NK cells, resulting in a misbalance of immature NK cell subpopulations and higher susceptibility to apoptosis of NK cells. [13]

NKG2D is involved in the generation of peripheral tolerance by the effective downregulation of NKG2D ligands, for the prevention from recognition by NK cells. It is supposed to act as a form of obstacle against NK cells' hyper-responsiveness to ligands, without complete education in bone marrow. [38] Tolerance of NK cells is likewise observed during pregnancy, when placenta produces soluble and exosome-bound ligands for NKG2D and accumulates large number of NK cells which prevent recognition of fetus as non-self. [39]

NKG2D and T cells

For priming of T cells, binding of ligand on T cell receptors (TCR), co-stimulation by membrane receptors and cytokines are all necessary components. Co-stimulation regulates responsiveness of T cells and NKG2D is one of well-documented co-stimulatory molecules for T cells., [40] CD28 –mediated co-stimulation is required for promotion of cytokine production and cytotoxicity in CD8+ T cells by NKG2D. [41] For cytokine production and cytolytic killing by γδ T cells,  priming is not required, however NKG2D expression is constitutive while solely triggering NKG2D in γδ T cells does not mediate cytotoxicity. [42]

In T cells, NKG2D is associated with IL15-receptor signaling and also with the development of memory CD8 T cells. [43] Key role in the transformation of CD8+ T cells into effector or memory types is played by mammalian target of rapamycin complex 1 (mTORC1) – memory precursor cells are characteristic by the low level of mTORC1 and for terminally differentiated CD8+ T cells, high level of mTORC1 activity is typical. [44] Upregulation of antiapoptic Mcl-1 protein by NKG2D also induces formation of memory T cells. [43] In  murine memory T cell precursors, downregulation of T-bet transcription factor is likewise affected by NKG2D. [45]

NKG2D and B cells

Also development of B cells is regulated by NKG2D—NKG2D deficient mice have reduced number of B cells in spleen, [46] which is partially depended on DAP10. [47] In comparison to NK cells, mature B cells do not express NKG2D. [46]

See also

Related Research Articles

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cell and other intracellular pathogens acting at around 3 days after infection, and respond to tumor formation. Typically, immune cells detect the major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing the death of the infected cell by lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class 1. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

Killer-cell immunoglobulin-like receptors (KIRs), are a family of type I transmembrane glycoproteins expressed on the plasma membrane of natural killer (NK) cells and a minority of T cells. At least 15 genes and 2 pseudogenes encoding KIR map in a 150-kb region of the leukocyte receptor complex (LRC) on human chromosome 19q13.4.

Siglecs(Sialic acid-binding immunoglobulin-type lectins) are cell surface proteins that bind sialic acid. They are found primarily on the surface of immune cells and are a subset of the I-type lectins. There are 14 different mammalian Siglecs, providing an array of different functions based on cell surface receptor-ligand interactions.

NKG2 also known as CD159 is a receptor for natural killer cells. There are 7 NKG2 types: A, B, C, D, E, F and H. NKG2D is an activating receptor on the NK cell surface. NKG2A dimerizes with CD94 to make an inhibitory receptor (CD94/NKG2).

<span class="mw-page-title-main">MHC class I polypeptide–related sequence A</span>

MHC class I polypeptide–related sequence A (MICA) is a highly polymorphic cell surface glycoprotein encoded by the MICA gene located within MHC locus. MICA is related to MHC class I and it has similar domain structure, however, it is not associated with β2-microglobulin nor binds peptides as conventional MHC class I molecules do. MICA rather functions as a stress-induced ligand (as a danger signal) for integral membrane protein receptor NKG2D ("natural-killer group 2, member D"). MICA is broadly recognized by NK cells, γδ T cells, and CD8+ αβ T cells which carry NKG2D receptor on their cell surface and which are activated via this interaction.

<span class="mw-page-title-main">CD69</span>

CD69 is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentiation as well as lymphocyte retention in lymphoid organs.

<span class="mw-page-title-main">KLRC4</span>

NKG2-F type II integral membrane protein is a protein that in humans is encoded by the KLRC4 gene.

<span class="mw-page-title-main">KLRC2</span>

NKG2-C type II integral membrane protein or NKG2C is a protein that in humans is encoded by the KLRC2 gene. It is also known as or cluster of differentiation 159c (CD159c).

<span class="mw-page-title-main">HCST (gene)</span> Protein-coding gene in the species Homo sapiens

Hematopoietic cell signal transducer is a protein that in humans is encoded by the HCST gene.

<span class="mw-page-title-main">ULBP2</span>

UL16 binding protein 2 (ULBP2) is a cell surface glycoprotein encoded by ULBP2 gene located on the chromosome 6. ULBP2 is related to MHC class I molecules, but its gene maps outside the MHC locus. The domain structure of ULBP2 differs significantly from those of conventional MHC class I molecules. It does not contain the α3 domain and the transmembrane segment. ULBP2 is thus composed of only the α1α2 domain which is linked to the cell membrane by the GPI anchor.

<span class="mw-page-title-main">ULBP1</span>

UL16 binding protein 1 (ULBP1) is a cell surface glycoprotein encoded by ULBP1 gene located on the chromosome 6. ULBP1 is related to MHC class I molecules, but its gene maps outside the MHC locus. The domain structure of ULBP1 differs significantly from those of conventional MHC class I molecules. It does not contain the α3 domain and the transmembrane segment. ULBP1 is thus composed of only the α1α2 domain which is linked to the cell membrane by the GPI anchor. It functions as a stress-induced ligand for NKG2D receptor. ULBP1 is, for example, upregulated during HCMV infection. Binding of HCMV-encoded UL16 glycoprotein to ULBP1 interferes with cell surface localization of ULBP1; this represents another mechanism by which HCMV-infected cells might escape the immune system.

<span class="mw-page-title-main">TNFRSF18</span>

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.

<span class="mw-page-title-main">RAET1E</span>

Retinoic acid early transcript 1E(RAET1E) is a cell surface glycoprotein encoded by RAET1E gene located on the chromosome 6. RAET1E is related to MHC class I molecules, but its gene maps outside the MHC locus. RAET1E is composed of external α1α2 domain, transmembrane segment and C-terminal cytoplasmic tail. RAET1E functions as a stress-induced ligand for NKG2D receptor.

<span class="mw-page-title-main">ULBP3</span>

UL16 binding protein 3 (ULBP3) is a cell surface glycoprotein encoded by ULBP3 gene located on the chromosome 6. ULBP3 is related to MHC class I molecules, but its gene maps outside the MHC locus. The domain structure of ULBP3 differs significantly from those of conventional MHC class I molecules. It does not contain the α3 domain and the transmembrane segment. ULBP3 is thus composed of only the α1α2 domain which is linked to the cell membrane by the GPI anchor. It functions as a stress-induced ligand for NKG2D receptor.

Immunoevasins are proteins expressed by some viruses that enable the virus to evade immune recognition by interfering with MHC I complexes in the infected cell, therefore blocking the recognition of viral protein fragments by CD8+ cytotoxic T lymphocytes. Less frequently, MHC II antigen presentation and induced-self molecules may also be targeted. Some viral immunoevasins block peptide entry into the endoplasmic reticulum (ER) by targeting the TAP transporters. Immunoevasins are particularly abundant in viruses that are capable of establishing long-term infections of the host, such as herpesviruses.

<span class="mw-page-title-main">Killer activation receptor</span> Class of protein

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Induced-self antigen is a marker of abnormal self, which can be recognized upon infected and transformed cells. Therefore, the recognition of "induced self" is an important strategy for surveillance of infection or tumor transformation - it results in elimination of the affected cells by activated NK cells or other immunological mechanisms. Similarly γδ T cells can recognize induced-self antigens expressed on cells under stress conditions.

CD94/NKG2 is a family of C-type lectin receptors which are expressed predominantly on the surface of NK cells and a subset of CD8+ T-lymphocyte. These receptors stimulate or inhibit cytotoxic activity of NK cells, therefore they are divided into activating and inhibitory receptors according to their function. CD94/NKG2 recognize nonclassical MHC glycoproteins class I (HLA-E in human and Qa-1 molecules in the mouse).

<span class="mw-page-title-main">Adaptive NK cell</span> Specialized subtype of cytotoxic lymphocyte

An adaptive natural killer (NK) cell or memory-like NK cell is a specialized natural killer cell that has the potential to form immunological memory. They can be distinguished from cytotoxic NK (cNK) cells by their receptor expression profile and epigenome. Adaptive NK cells are so named for properties which they share with the adaptive immune system. Though adaptive NK cells do not possess antigen specificity, they exhibit dynamic expansions of defined cell subsets, increased proliferation and long-term persistence for up to 3 months in vivo, high IFN-γ production, potent cytotoxic activity upon ex vivo restimulation, and protective memory responses.

<span class="mw-page-title-main">Paired receptors</span>

Paired receptors are pairs or clusters of receptor proteins that bind to extracellular ligands but have opposing activating and inhibitory signaling effects. Traditionally, paired receptors are defined as homologous pairs with similar extracellular domains and different cytoplasmic regions, whose genes are located together in the genome as part of the same gene cluster and which evolved through gene duplication. Homologous paired receptors often, but not always, have a shared ligand in common. More broadly, pairs of receptors have been identified that exhibit paired functional behavior - responding to a shared ligand with opposing intracellular signals - but are not closely homologous or co-located in the genome. Paired receptors are highly expressed in the cells of the immune system, especially natural killer (NK) and myeloid cells, and are involved in immune regulation.

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