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HLA-G

Developmental stage

Expressed at the morula stage (at protein level) (PubMed:29262349). Expressed in extravillous trophoblast and cytotrophoblast (PubMed:16210391, PubMed:26460007, PubMed:7589701). Expressed in fetal eye and thymus (PubMed:2336406).

Isoform 7

Expressed in fetal liver.

Domain

The VL9 peptide/epitope (VMAPRTLFL) derived from the signal sequence is loaded onto HLA-E and enables HLA-E expression at the plasma membrane. Confers strong recognition by KLRD1-KLRC1 or KLRD1-KLRC2 receptors on NK cells.

Function

Isoform 1

Non-classical major histocompatibility class Ib molecule involved in immune regulatory processes at the maternal-fetal interface (PubMed:19304799, PubMed:23184984, PubMed:29262349). 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:16366734, PubMed:19304799, PubMed:20448110, PubMed:23184984, PubMed:27859042, PubMed:29262349). 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:16366734, PubMed:19304799, PubMed:23184984, PubMed:29262349). Through interaction with KIR2DL4 receptor on decidual macrophages induces pro-inflammatory 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:19304799, PubMed:23184984, PubMed:29262349). 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:16366734, PubMed:19304799, PubMed:20448110, PubMed:23184984, PubMed:29262349). 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:16366734, PubMed:19304799, PubMed:23184984, PubMed:29262349). Through interaction with KIR2DL4 receptor on decidual macrophages induces pro-inflammatory 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.

Post-translational modifications

N-glycosylated.

Soluble HLA class I histocompatibility antigen, alpha chain G

Produced by proteolytic cleavage at the cell surface (shedding) by matrix metalloproteinase MMP2.

Sequence Similarities

Belongs to the MHC class I family.

Tissue Specificity

Expressed in adult eye (PubMed:1570318). Expressed in immune cell subsets including monocytes, myeloid and plasmacytoid dendritic cells and regulatory T cells (Tr1)(at protein level) (PubMed:20448110). Secreted by follicular dendritic cell and follicular helper T cells (PubMed:24453251).

Isoform 5

Detected in physiological fluids including amniotic fluid and serum.

Isoform 7

Expressed in placenta, amniotic membrane, skin, cord blood and peripheral blood mononuclear cells.

Cellular localization

Alternative names

HLA-6.0, HLAG, HLA-G, HLA G antigen, MHC class I antigen G

swissprot:P17693 entrezGene:3135 omim:142800 omim:142871 swissprot:P01889 swissprot:P30443 entrezGene:3105 swissprot:P30499 entrezGene:3107 entrezGene:3106

Other research areas