HLA-G

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.[5]

HLA-G
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3KYO, 1YDP, 2D31, 2DYP, 3BZE, 3CDG, 3CII, 3KYN
Identifiers
Aliases	HLA-G, MHC-G, major histocompatibility complex, class I, G
External IDs	OMIM: 142871 MGI: 95915 HomoloGene: 133255 GeneCards: HLA-G
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6p22.1 Start 29,826,967 bp[1] End 29,831,125 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17 B1|17 19.16 cM Start 37,270,220 bp[2] End 37,274,484 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • protein homodimerization activity • receptor binding • peptide antigen binding • GO:0001948 protein binding • identical protein binding • CD8 receptor binding Cellular component • integral component of membrane • phagocytic vesicle membrane • early endosome membrane • membrane • Golgi membrane • MHC class I protein complex • ER to Golgi transport vesicle membrane • integral component of lumenal side of endoplasmic reticulum membrane • recycling endosome membrane • extracellular region • cell membrane • endosome • early endosome • endoplasmic reticulum • endoplasmic reticulum membrane • filopodium membrane • cis-Golgi network membrane • cell projection • extracellular • external side of plasma membrane Biological process • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent • positive regulation of tolerance induction • positive regulation of interleukin-12 production • interferon-gamma-mediated signaling pathway • immune system process • positive regulation of regulatory T cell differentiation • positive regulation of T cell tolerance induction • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-independent • cellular defense response • negative regulation of T cell proliferation • negative regulation of immune response • type I interferon signaling pathway • regulation of immune response • immune response-inhibiting cell surface receptor signaling pathway • negative regulation of dendritic cell differentiation • antigen processing and presentation of peptide antigen via MHC class I • negative regulation of T cell mediated cytotoxicity • positive regulation of T cell mediated cytotoxicity • peripheral B cell tolerance induction • antigen processing and presentation of endogenous peptide antigen via MHC class Ib • positive regulation of natural killer cell cytokine production • immune response • negative regulation of angiogenesis • protection from natural killer cell mediated cytotoxicity • negative regulation of natural killer cell mediated cytotoxicity • negative regulation of protein kinase B signaling • positive regulation of macrophage cytokine production • protein homotrimerization • negative regulation of G0 to G1 transition • positive regulation of endothelial cell apoptotic process • positive regulation of cellular senescence • antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	3135	14991
Ensembl	ENSG00000230413 ENSG00000233095 ENSG00000237216 ENSG00000276051 ENSG00000204632 ENSG00000235346 ENSG00000235680 ENSG00000206506	ENSMUSG00000016206
UniProt	P17693	Q31093
RefSeq (mRNA)	NM_002127 NM_001363567	NM_013819
RefSeq (protein)	NP_002118 NP_001350496	NP_038847
Location (UCSC)	Chr 6: 29.83 – 29.83 Mb	Chr 17: 37.27 – 37.27 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[5] Exon 7 and 8 are not translated due to a stop codon present in exon 6.[6]

Function

HLA-G may play a role in immune tolerance in pregnancy, being expressed in the placenta by extravillous trophoblast cells (EVT), while the classical MHC class I genes (HLA-A and HLA-B) are not.[7] As HLA-G was first identified in placenta samples, many studies have evaluated its role in pregnancy disorders, such as preeclampsia and recurrent pregnancy loss.[8] Its downregulation is related to 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.[9]

However, a large 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.[10][11] 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.[12] Also, some higher primates do not show all MHC-G isoforms.[13] 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.[14] 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.[15] 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.[15]

Interactions

HLA-G has been shown to interact with CD8A.[16][17]

References

1. ENSG00000233095, ENSG00000237216, ENSG00000276051, ENSG00000204632, ENSG00000235346, ENSG00000235680, ENSG00000206506 GRCh38: Ensembl release 89: ENSG00000230413, ENSG00000233095, ENSG00000237216, ENSG00000276051, ENSG00000204632, ENSG00000235346, ENSG00000235680, ENSG00000206506 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000016206 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: HLA-G HLA-G histocompatibility antigen, class I, G".
6. Castelli, Erick C.; Mendes-Junior, Celso T.; Veiga-Castelli, Luciana C.; Roger, Michel; Moreau, Philippe; Donadi, Eduardo A. (2011-11-01). "A Comprehensive Study of Polymorphic Sites along the HLA-G Gene: Implication for Gene Regulation and Evolution". Molecular Biology and Evolution. 28 (11): 3069–3086. doi:10.1093/molbev/msr138. ISSN 0737-4038. PMID 21622995.
7. Jay Iams; Creasy, Robert K.; Resnik, Robert; Robert Reznik (2004). Maternal-fetal medicine. Philadelphia: W.B. Saunders Co. pp. 31–32. ISBN 978-0-7216-0004-8.
8. Michita, Rafael Tomoya; Zambra, Francis Maria Báo; Fraga, Lucas Rosa; Sanseverino, Maria Teresa Vieira; Callegari-Jacques, Sidia Maria; Vianna, Priscila; Chies, José Artur Bogo (2016). "A tug-of-war between tolerance and rejection – New evidence for 3′UTR HLA-G haplotypes influence in recurrent pregnancy loss". Human Immunology. 77 (10): 892–897. doi:10.1016/j.humimm.2016.07.004. PMID 27397898.
9. 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.CS1 maint: multiple names: authors list (link)
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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. doi:10.1042/bst0280208. 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. pp. 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.