HLA-G

Major histocompatibility complex, class I, G
PDB rendering based on 1ydp.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1YDP​, 2D31​, 2DYP​, 3BZE​, 3CDG​, 3CII​, 3KYN​, 3KYO​
Identifiers
Symbols	HLA-G ; MHC-G
External IDs	OMIM: 142871 MGI: 95936 HomoloGene: 133255 GeneCards: HLA-G Gene
Gene ontology Molecular function • receptor binding • peptide antigen binding • protein homodimerization activity Cellular component • Golgi membrane • plasma membrane • ER to Golgi transport vesicle membrane • membrane • phagocytic vesicle membrane • early endosome membrane • MHC class I protein complex • integral component of lumenal side of endoplasmic reticulum membrane Biological process • antigen processing and presentation of peptide antigen via MHC class I • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-independent • positive regulation of tolerance induction • positive regulation of T cell tolerance induction • immune response-inhibiting cell surface receptor signaling pathway • cellular defense response • cytokine-mediated signaling pathway • positive regulation of interleukin-12 production • negative regulation of T cell proliferation • antigen processing and presentation of exogenous peptide antigen via MHC class I • positive regulation of regulatory T cell differentiation • regulation of immune response • negative regulation of immune response • interferon-gamma-mediated signaling pathway • type I interferon signaling pathway • negative regulation of dendritic cell differentiation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3135	14991
Ensembl	ENSG00000204632	ENSMUSG00000016206
UniProt	P17693	Q0WXH3
RefSeq (mRNA)	NM_002127	NM_013819
RefSeq (protein)	NP_002118	NP_038847
Location (UCSC)	Chr 6: 29.83 – 29.83 Mb	Chr 17: 37.27 – 37.27 Mb
PubMed search

MAP SHOWING HLA-G*01:05N ALLELE FREQUENCIES IN WORLD POPULATIONS

HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans is encoded by the HLA-G gene.^[1]

HLA-G belongs to the HLA nonclassical 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.^[1]

Function

HLA-G may play a role in immune tolerance in pregnancy, being expressed in the placenta, while the classical MHC class I genes HLA-A and HLA-B are not.^[2] HLA-A and -B downregulation results in protection from cytotoxic T cell responses, but would in theory result in a missing self response by natural killer cells. HLA-G is a ligand for NK cell inhibitory receptor KIR2DL4, and therefore expression of this HLA by the trophoblast defends it against NK cell-mediated death.^[3]

However, a big family with several members bearing only "null" HLA-G alleles has been found. None of these homozygous subjects have pregnancy or birth difficulties; nor do they present immunodeficiencies, autoimmune diseases, or tumors.^[4][5] It is striking that this "null" allele (HLA-G*01:05N), while it is quite frequent in some populations, like in Iranians, it is almost absent in some Amerindian populations.^[6] Also, some higher primates do not show all MHC-G isoforms.^[7] In addition, Cercopithecinae middle-sized Old World monkeys do not bear full MHC-G molecules since all of these monkeys present stop codons at MHC-G DNA.^[8] All of these anomalies must be studied.

The presence of soluble HLA-G (sHLA-G) in embryos is associated with better pregnancy rates. In order to optimize pregnancy rates, there is significant evidence that a morphological scoring system is the best strategy for the selection of embryos.^[9] However, presence of soluble HLA-G might be considered as a second parameter if a choice has to be made between embryos of morphologically equal quality.^[9]

Interactions

HLA-G has been shown to interact with CD8A.^[10][11]

References

1. "Entrez Gene: HLA-G HLA-G histocompatibility antigen, class I, G".
2. Jay Iams; Creasy, Robert K.; Resnik, Robert; Robert Reznik (2004). Maternal-fetal medicine. Philadelphia: W.B. Saunders Co. pp. 31–32. ISBN 0-7216-0004-2.
3. Lash, G, Robson, S, Bulmer, J. (2010). "Review: Functional role of uterine natural killer (uNK) cells in human early pregnancy decidua". Placenta 31 (S): 87–92. doi:10.1016/j.placenta.2009.12.022. PMID 20061017.
4. Suárez MB, Morales P, Castro MJ, Fernández V, Varela P, Alvarez M, Martínez-Laso J, Arnaiz-Villena A (1997). "A new HLA-G allele (HLA-G*0105N) and its distribution in the Spanish population". Immunogenetics 45 (6): 464–5. doi:10.1007/s002510050235. PMID 9089111.
5. Casro MJ, Morales P, Rojo-Amigo R, Martinez-Laso J, Allende L, Varela P, Garcia-Berciano M, Guillen-Perales J, Arnaiz-Villena A (September 2000). "Homozygous HLA-G*0105N healthy individuals indicate that membrane-anchored HLA-G1 molecule is not necessary for survival". Tissue Antigens 56 (3): 232–9. doi:10.1034/j.1399-0039.2000.560305.x. PMID 11034559.
6. Arnaiz-Villena A, Enriquez-de-Salamanca M, Areces C, Alonso-Rubio J, Abd-El-Fatah-Khalil S, Fernandez-Honrado M, Rey D (April 2013). "HLA-G(∗)01:05N null allele in Mayans (Guatemala) and Uros (Titikaka Lake, Peru): Evolution and population genetics". Hum. Immunol. 74 (4): 478–82. doi:10.1016/j.humimm.2012.12.013. PMID 23261410.
7. Castro MJ, Morales P, Martinez-Laso J, Allende L, Rojo-Amigo R, Gonzalez-Hevilla M, Varela P, Moscoso J, Garcia-Berciano M, Arnaiz-Villena A (November 2000). "Lack of MHC-G4 and soluble (G5, G6) isoforms in the higher primates, Pongidae". Hum. Immunol. 61 (11): 1164–8. doi:10.1016/s0198-8859(00)00189-0. PMID 11137222.
8. Castro MJ, Morales P, Fernández-Soria V, Suarez B, Recio MJ, Alvarez M, Martín-Villa M, Arnaiz-Villena A (1996). "Allelic diversity at the primate Mhc-G locus: exon 3 bears stop codons in all Cercopithecinae sequences". Immunogenetics 43 (6): 327–36. doi:10.1007/bf02199801. PMID 8606053.
9. Rebmann V, Switala M, Eue I, Grosse-Wilde H (May 2010). "Soluble HLA-G is an independent factor for the prediction of pregnancy outcome after ART: a German multi-centre study". Hum Reprod 25 (7): 1691–8. doi:10.1093/humrep/deq120. PMID 20488801.
10. Gao GF, Willcox BE, Wyer JR, Boulter JM, O'Callaghan CA, Maenaka K, Stuart DI, Jones EY, Van Der Merwe PA, Bell JI, Jakobsen BK (May 2000). "Classical and nonclassical class I major histocompatibility complex molecules exhibit subtle conformational differences that affect binding to CD8alphaalpha". J. Biol. Chem. 275 (20): 15232–8. doi:10.1074/jbc.275.20.15232. PMID 10809759.
11. Sanders SK, Giblin PA, Kavathas P (September 1991). "Cell-cell adhesion mediated by CD8 and human histocompatibility leukocyte antigen G, a nonclassical major histocompatibility complex class 1 molecule on cytotrophoblasts". J. Exp. Med. 174 (3): 737–40. doi:10.1084/jem.174.3.737. PMC 2118947. PMID 1908512.

Further reading

• Carosella ED, Favier B, Rouas-Freiss N, Moreau P, LeMaoult J (2008). "Beyond the increasing complexity of the immunomodulatory HLA-G molecule". Blood 111 (10): 4862–70. doi:10.1182/blood-2007-12-127662. PMID 18334671.
• Carosella ED, Moreau P, LeMaoult J, Rouas-Freiss N (2008). "HLA-G: From biology to clinical benefits". Trends in Immunology 29 (3): 125–32. doi:10.1016/j.it.2007.11.005. PMID 18249584.

• Arnaiz-Villena A, Martinez-Laso J, Alvarez M, et al. (1997). "Primate Mhc-E and -G alleles". Immunogenetics 46 (4): 251–66. doi:10.1007/s002510050271. PMID 9218527.
• Le Bouteiller P (2000). "HLA-G in the human placenta: expression and potential functions". Biochem. Soc. Trans. 28 (2): 208–12. PMID 10816129.
• Geyer M, Fackler OT, Peterlin BM (2001). "Structure–function relationships in HIV-1 Nef". EMBO Rep. 2 (7): 580–5. doi:10.1093/embo-reports/kve141. PMC 1083955. PMID 11463741.
• Langat DK, Hunt JS (2003). "Do nonhuman primates comprise appropriate experimental models for studying the function of human leukocyte antigen-G?". Biol. Reprod. 67 (5): 1367–74. doi:10.1095/biolreprod.102.005587. PMID 12390864.
• Moreau P, Dausset J, Carosella ED, Rouas-Freiss N (2003). "Viewpoint on the functionality of the human leukocyte antigen-G null allele at the fetal-maternal interface". Biol. Reprod. 67 (5): 1375–8. doi:10.1095/biolreprod.102.005439. PMID 12390865.
• Moreau P, Rousseau P, Rouas-Freiss N, et al. (2002). "HLA-G protein processing and transport to the cell surface". Cell. Mol. Life Sci. 59 (9): 1460–6. doi:10.1007/s00018-002-8521-8. PMID 12440768.
• Greenway AL, Holloway G, McPhee DA, et al. (2004). "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". J. Biosci. 28 (3): 323–35. doi:10.1007/BF02970151. PMID 12734410.
• Bénichou S, Benmerah A (2003). "[The HIV nef and the Kaposi-sarcoma-associated virus K3/K5 proteins: "parasites"of the endocytosis pathway]". Med Sci (Paris) 19 (1): 100–6. doi:10.1051/medsci/2003191100. PMID 12836198.
• Le Bouteiller P, Legrand-Abravanel F, Solier C (2004). "Soluble HLA-G1 at the materno-foetal interface--a review". Placenta. 24 Suppl A: S10–5. doi:10.1053/plac.2002.0931. PMID 12842408.
• Sköld M, Behar SM (2003). "Role of CD1d-Restricted NKT Cells in Microbial Immunity". Infect. Immun. 71 (10): 5447–55. doi:10.1128/IAI.71.10.5447-5455.2003. PMC 201095. PMID 14500461.
• Wiendl H, Mitsdoerffer M, Weller M (2004). "Express and protect yourself: the potential role of HLA-G on muscle cells and in inflammatory myopathies". Hum. Immunol. 64 (11): 1050–6. doi:10.1016/j.humimm.2003.07.001. PMID 14602235.
• Urosevic M, Dummer R (2004). "HLA-G in skin cancer: a wolf in sheep's clothing?". Hum. Immunol. 64 (11): 1073–80. doi:10.1016/j.humimm.2003.08.351. PMID 14602238.
• Carosella ED, Moreau P, Le Maoult J, et al. (2004). "HLA-G molecules: from maternal-fetal tolerance to tissue acceptance". Adv. Immunol. Advances in Immunology 81: 199–252. doi:10.1016/S0065-2776(03)81006-4. ISBN 978-0-12-022481-4. PMID 14711057.
• Leavitt SA, SchOn A, Klein JC, et al. (2004). "Interactions of HIV-1 proteins gp120 and Nef with cellular partners define a novel allosteric paradigm". Curr. Protein Pept. Sci. 5 (1): 1–8. doi:10.2174/1389203043486955. PMID 14965316.
• Le Maoult J, Rouas-Freiss N, Le Discorde M, et al. (2004). "[HLA-G in organ transplantation]". Pathol. Biol. 52 (2): 97–103. doi:10.1016/j.patbio.2003.04.006. PMID 15001239.
• Tolstrup M, Ostergaard L, Laursen AL, et al. (2004). "HIV/SIV escape from immune surveillance: focus on Nef". Curr. HIV Res. 2 (2): 141–51. doi:10.2174/1570162043484924. PMID 15078178.
• Joseph AM, Kumar M, Mitra D (2005). "Nef: "necessary and enforcing factor" in HIV infection". Curr. HIV Res. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726.
• McIntire RH, Hunt JS (2005). "Antigen presenting cells and HLA-G--a review". Placenta. 26 Suppl A: S104–9. doi:10.1016/j.placenta.2005.01.006. PMID 15837058.
• Anderson JL, Hope TJ (2005). "HIV accessory proteins and surviving the host cell". Current HIV/AIDS reports 1 (1): 47–53. doi:10.1007/s11904-004-0007-x. PMID 16091223.