HLA-G
HLA-G belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-G is expressed on fetal derived placental cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail. [provided by RefSeq, Jul 2008]
Function
Isoform 1:
Non-classical major histocompatibility class Ib molecule involved in immune regulatory processes at the maternal-fetal interface (PubMed:23184984, PubMed:29262349, PubMed:19304799).
In complex with B2M/beta-2 microglobulin binds a limited repertoire of nonamer self-peptides derived from intracellular proteins including histones and ribosomal proteins (PubMed:7584149, PubMed:8805247).
Peptide-bound HLA-G-B2M complex acts as a ligand for inhibitory/activating KIR2DL4, LILRB1 and LILRB2 receptors on uterine immune cells to promote fetal development while maintaining maternal-fetal tolerance (PubMed:23184984, PubMed:29262349, PubMed:16366734, PubMed:19304799, PubMed:20448110, PubMed:27859042).
Upon interaction with KIR2DL4 and LILRB1 receptors on decidual NK cells, it triggers NK cell senescence-associated secretory phenotype as a molecular switch to promote vascular remodeling and fetal growth in early pregnancy (PubMed:23184984, PubMed:29262349, PubMed:16366734, PubMed:19304799).
Through interaction with KIR2DL4 receptor on decidual macrophages induces proinflammatory cytokine production mainly associated with tissue remodeling (PubMed:19304799).
Through interaction with LILRB2 receptor triggers differentiation of type 1 regulatory T cells and myeloid-derived suppressor cells, both of which actively maintain maternal-fetal tolerance (PubMed:20448110, PubMed:27859042).
May play a role in balancing tolerance and antiviral-immunity at maternal-fetal interface by keeping in check the effector functions of NK, CD8+ T cells and B cells (PubMed:10190900, PubMed:11290782, PubMed:24453251).
Reprograms B cells toward an immune suppressive phenotype via LILRB1 (PubMed:24453251).
May induce immune activation/suppression via intercellular membrane transfer (trogocytosis), likely enabling interaction with KIR2DL4, which resides mostly in endosomes (PubMed:20179272, PubMed:26460007).
Through interaction with the inhibitory receptor CD160 on endothelial cells may control angiogenesis in immune privileged sites (PubMed:16809620).
Isoform 2:
Likely does not bind B2M and presents peptides. Negatively regulates NK cell- and CD8+ T cell-mediated cytotoxicity (PubMed:11290782).
Isoform 3:
Likely does not bind B2M and presents peptides. Negatively regulates NK cell- and CD8+ T cell-mediated cytotoxicity (PubMed:11290782).
Isoform 4:
Likely does not bind B2M and presents peptides. Negatively regulates NK cell- and CD8+ T cell-mediated cytotoxicity (PubMed:11290782).
Isoform 5:
Non-classical major histocompatibility class Ib molecule involved in immune regulatory processes at the maternal-fetal interface (PubMed:23184984, PubMed:29262349, PubMed:19304799).
In complex with B2M/beta-2 microglobulin binds a limited repertoire of nonamer self-peptides derived from intracellular proteins including histones and ribosomal proteins (PubMed:7584149, PubMed:8805247).
Peptide-bound HLA-G-B2M complex acts as a ligand for inhibitory/activating KIR2DL4, LILRB1 and LILRB2 receptors on uterine immune cells to promote fetal development while maintaining maternal-fetal tolerance (PubMed:23184984, PubMed:29262349, PubMed:16366734, PubMed:19304799, PubMed:20448110).
Upon interaction with KIR2DL4 and LILRB1 receptors on decidual NK cells, it triggers NK cell senescence-associated secretory phenotype as a molecular switch to promote vascular remodeling and fetal growth in early pregnancy (PubMed:23184984, PubMed:29262349, PubMed:16366734, PubMed:19304799).
Through interaction with KIR2DL4 receptor on decidual macrophages induces proinflammatory cytokine production mainly associated with tissue remodeling (PubMed:19304799).
Through interaction with LILRB2 receptor triggers differentiation of type 1 regulatory T cells and myeloid-derived suppressor cells, both of which actively maintain maternal-fetal tolerance (PubMed:20448110).
Reprograms B cells toward an immune suppressive phenotype via LILRB1 (PubMed:24453251).
Isoform 6:
Likely does not bind B2M and presents peptides.
Isoform 7:
Likely does not bind B2M and presents peptides.
Biological Process
Antigen processing and presentation of endogenous peptide antigen via MHC class Ib Source: UniProtKB
Antigen processing and presentation of peptide antigen via MHC class I Source: UniProtKB-KW
Cellular defense response Source: ProtInc
Immune response-inhibiting cell surface receptor signaling pathway Source: BHF-UCL
Negative regulation of angiogenesis Source: UniProtKB
Negative regulation of dendritic cell differentiation Source: BHF-UCL
Negative regulation of G0 to G1 transition Source: UniProtKB
Negative regulation of immune response Source: UniProtKB
Negative regulation of natural killer cell mediated cytotoxicity Source: UniProtKB
Negative regulation of protein kinase B signaling Source: UniProtKB
Negative regulation of T cell mediated cytotoxicity Source: UniProtKB
Negative regulation of T cell proliferation Source: BHF-UCL
Peripheral B cell tolerance induction Source: UniProtKB
Positive regulation of cellular senescence Source: UniProtKB
Positive regulation of endothelial cell apoptotic process Source: UniProtKB
Positive regulation of interleukin-12 production Source: BHF-UCL
Positive regulation of macrophage cytokine production Source: UniProtKB
Positive regulation of natural killer cell cytokine production Source: UniProtKB
Positive regulation of regulatory T cell differentiation Source: BHF-UCL
Positive regulation of T cell tolerance induction Source: BHF-UCL
Positive regulation of tolerance induction Source: UniProtKB
Protection from natural killer cell mediated cytotoxicity Source: UniProtKB
Protein homotrimerization Source: UniProtKB
Cellular Location
Isoform 1: Cell membrane; Early endosome membrane; Endoplasmic reticulum membrane
Chain Soluble HLA class I histocompatibility antigen, alpha chain G: Secreted
Isoform 2: Cell membrane
Isoform 3: Cell membrane
Isoform 4: Cell membrane
Isoform 5: Secreted; Early endosome
Isoform 6: Secreted
Isoform 7: Secreted; Filopodium membrane. HLA-G trogocytosis from extravillous trophoblast's filopodia occurs in the majority of decidual NK cells.
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