HLA-F
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| Location (UCSC) | Chr 6: 29.72 – 29.74 Mb | n/a | |||||||
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HLA class I histocompatibility antigen, alpha chain F is a protein that in humans is encoded by the HLA-F gene.[4][5] It is an empty intracellular molecule that encodes a non-classical heavy chain anchored to the membrane and forming a heterodimer with a β-2 microglobulin light chain. It belongs to the HLA class I heavy chain paralogues that separate from most of the HLA heavy chains. HLA-F is localized in the endoplasmic reticulum and Golgi apparatus, and is also unique in the sense that it exhibits few polymorphisms in the human population relative to the other HLA genes; however, there have been found different isoforms from numerous transcript variants found for the HLA-F gene. Its pathways include IFN-gamma signaling and CDK-mediated phosphorylation (cyclin-dependent kinase) and removal of the Saccharomyces cerevisiae Cdc6 protein, which is crucial for functional DNA replication.[6]
HLA-F
The Major Histocompatibility Complex (MHC) is a group of cell surface proteins that in humans is also called the Human Leukocyte Antigen (HLA) complex. These proteins are encoded by a cluster of genes known as the HLA locus. The HLA locus occupies a ~ 3Mbp stretch that is located on the short arm of chromosome 6, specifically on 6p21.1-21.3.
Gene
The HLA-F gene is located on the short arm of
Protein
The HLA-F protein is a ~40-41 kDa molecule with conserved domains.[13] Exon 7 is absent from the mRNA of HLA-F.[4][14] The absence of this exon produces a modification in the cytoplasmic tail of the protein making it shorter relative to classical HLA class-I proteins.[4] The cytoplasmic tail helps HLA-F exit the endoplasmic reticulum,[15] and that function is primarily done by the amino acid valine found at the C-terminal end of the tail.[15][16]
Structure
The structure of HLA-F is similar to that of the other HLA class I genes, which consist of eight exons. Of the key residues likely to form from the floor of the groove, position 97 is a glycine whose residue is a single proton, whereas in most class Ia structures it is a charged residue and in HLA-E, it is a bulky hydrophobic tryptophan. If the HLA-F groove binds to a peptide, then the glycine residue will create space in the mid-portion of the groove which might allow larger side chains to fit and be accommodated . This nonclassical class I gene also has two histidine residues (His 114-His116) close together in the C-terminal groove floor, mirroring His-9-His99 in HLA-E. Tyr 7, Tyr 59, Tyr 159 and Tyr 171, which are typically involved in the hydrogen-bonding network to the peptide N-terminal residues, are conserved.[17]
The possible pocket regions of HLA-F include a situation where the A pocket is hydrophobic and similar to that of HLA-E, and pocket B retains Met 45 and Ala 67, which also characterize the HLA-E pocket and are likely to be hydrophobic and large. The C-pocket, however, differs significantly from that of the HLA-E with similarities to the C pocket of HLA-B8. In the D pocket region of this protein, the Asn 99 may favor a charged residue, but the other residues in this pocket, including phenylalanine make predictions hard to make. However, the F-pocket of HLA-F appears well conserved with HLA-E and the other class Ia molecules and likely favors an aliphatic group, such as leucine.[17][18]
Expression
Classic HLA class I molecules interact with HLA-F through their heavy chain.[16] However, HLA class I molecules only interact with HLA-F when they are in the form of an open conformer (free of peptide). Thus, HLA-F is expressed independently of bound peptide.[16][19]
Intracellular expression
HLA-F is expressed intracellularly in peripheral blood
Extracellular expression
HLA-F is expressed on the cell surface of
Expression during pregnancy
In the first trimester, HLA-F is weakly expressed in the trophoblastic elements residing outside the villi (extravillous trophoblast cells). Its expression increases and translocated onto the cell surface during the second trimester, coinciding with fetal growth which, in context, suggests it plays a role in development.[23]
Interaction with NK cells
HLA-F can be expressed in two ways on the cell surface: with β2m and a peptide as a complex of HLA-F heavy chain or without the peptide and β2m as an open conformer with just the heavy chain. It can transport from the endoplasmic reticulum partially with the aid of tapasin, independent from the TAP protein complex, typically associated with antigen processing and transportation. Open conformer (OC) HLA-Fs can form homodimers and heterodimers with distinct HLA class I OCs, which may suggest they are involved in cross-presentation of extracellular antigens.[24]
HLA OCs are able to bind to other receptors than the HLA complex with the β2m and peptide, most relevant to the diverse function of HLA-F. These receptors include binding inhibitory and activating immune receptors primarily expressed in natural killer (NK) cells, but also includes other immune cells. To do this, HLA OCs bind to the activating receptor KIR3DS1 and inhibitory receptor killer receptors 3DL1 and 3dL2.[18]
Recent studies further suggest that HLA-F also presents long peptides (7 to more than 30 amino acids) to T cell receptors. They are able to do this because of an amino acid substitution in position 62 that forms an open-ended groove with N-terminal extensions. It is still not known if there may be consequences for this in the immune regulation at the feto-maternal contact zone.[24]
Transcriptional regulation of HLA-F
In the promoter of HLA-F, both studied regulatory modules display homology to the classical MHC class I genes. HLA-F has a conserved κB1 site enhancer bound by NF- κB, but the HLA-F gene is not induced by NF- κB without flanking regulatory sequences (such as IRSE) that provide a helper function. The IRSE in HLA-F is homologous to other classical MHC class I genes. INF- γ also induces HLA-F with its IRSE (IFN-stimulated response element). Further, it is also induced by CIITA, a transcriptional coactivator that regulates the transcription of MHC class II genes.[25]
Function
HLA-F belongs to the non-classical HLA class I heavy chain paralogues. Compared to classical HLA class I molecules, it exhibits very few polymorphisms. This class I molecule mainly exists as a heterodimer associated with the invariant light chain β-2 microglobulin.
HLA-F is currently the most enigmatic of the HLA molecules. Hence, its precise functions still remain to be resolved. Though, in contrast to other HLA molecules, it mainly resides intracellularly and rarely reaches the cell surface, e.g. upon activation of
Association with specialized ligands
HLA-F has been observed only in a subset of cell membranes, mostly
Maternal immunity tolerance
It has been observed that all three non-classical HLA class I proteins are expressed in placental trophoblasts in contact with maternal immune cells.[8] This suggests that these proteins collaborate in the immune response and that HLA-F plays a fundamental role in both normal and maternal immune response.[8] HLA-F is also expressed in decidual extravillous trophoblasts.[23] During pregnancy, HLA-F interacts with T reg cells and extravillous trophoblasts mediating maternal tolerance to the fetus.[22]
Intermolecular communication
During the interaction between HLA-F and the heavy chain (HC) of HLA class I molecules in activated lymphocytes, HLA-F plays a role as a chaperone, escorting HLA class I HC to the cell surface and stabilizing its expression in the absence of peptide.[16] HLA-F binds most allelic forms of HLA class I open conformers, but it does not bind peptide complexes.[19]
The expression patterns of HLA-F in T cells suggest that HLA-F is involved in the communication pathway between T reg and activated T cells, where HLA-F signals that the immune response has been activated. During this communication, either HLA-F invokes secretion of inhibitory cytokines by the regulatory T cells or it provides a simple inhibitory signal to the regulatory T cells, allowing a normal immune response to proceed.[22]
Exogenous antigen cross-presentation
Viral proteins and other exogenous antigens decrease surface HLA-F expression because the exogenous proteins interact with HLA class I molecules at the same sites where HLA-F interacts, producing crosslinking. The exogenous proteins trigger an internal co-localization of both HLA-F and HLA class I molecules.[19] Exogenous proteins with higher affinity will interact more readily with HLA class I molecules triggering a dissociation of HLA class I/HLA-F, thereby reducing the surface levels of HLA-F.[19] HLA-F interacts with the open conformer (OC) of HLA class I and they function together in cross-presentation of exogenous antigen. Exogenous antigen binds to a structure on the surface of activated cells; this structure is composed of HLA class I open conformer and HLA-F; the peptide-binding point of contact is a specific HLA class I epitope on the exogenous antigen.[19]
Ligand during inflammatory response
The complex HLA-F/HLA class I OC has two distinct roles that are central to the inflammatory response: first, it is a ligand for KIR receptors and can both activate and inhibit KIR; second, it is involved in cross-presentation of exogenous antigen.[27][28][18]
The complex HLA-F/HLA class-I OC is a ligand for a subset of KIR (Killer-cell immunoglobulin-like receptor) receptors.[27] Specifically, it was demonstrated that HLA-F interacts physically and functionally with three KIR receptors: KIR3DL2, KIR2DS4, and KIR3DS1, particularly during the inflammatory response.[27][28][18] KIR directly interacts with both HLA-F and HLA class-I individually (i.e. no dimerization between HLA-F and HLA class-I is necessary).
Disease association
HLA-F has been linked to several diseases (Table). For
| disease | reference |
|---|---|
| gastric adenocarcinoma | [29] |
| breast cancer | [30] |
| esophageal carcinoma | [31] |
| lung cancer | [32] |
| hepatocellular carcinoma | [33] |
| neuroblastoma | [34] |
| hepatitis B | [35] |
| Systemic Lupus Erythematosus | [36] |
| Type 1 Diabetes | [37] |
References
- ^ a b c ENSG00000237508, ENSG00000234487, ENSG00000206509, ENSG00000137403, ENSG00000235220, ENSG00000204642 GRCh38: Ensembl release 89: ENSG00000229698, ENSG00000237508, ENSG00000234487, ENSG00000206509, ENSG00000137403, ENSG00000235220, ENSG00000204642 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 1688605.
- ^ a b "Entrez Gene: HLA-F major histocompatibility complex, class I, F".
- ^ PMID 12213342.
- ISBN 978-1-4496-5985-1.
- ^ S2CID 22308414.
- PMID 16434165.
- ^ PMID 2562983.
- PMID 3480534.
- PMID 15289473.
- ^ PMID 10605026.
- S2CID 6160579.
- ^ PMID 16709803.
- ^ PMID 20483783.
- ^ PMID 28636965.
- ^ PMID 27455421.
- ^ PMID 23851683.
- ^ PMID 14607927.
- ^ S2CID 42462661.
- ^ PMID 20865824.
- ^ PMID 12874228.
- ^ PMID 27649529.
- PMID 32010122.
- S2CID 203568247.
- ^ PMID 24018270.
- ^ PMID 27649529.
- ^ PMID 25862890.
- ^ PMID 26332651.
- ^ S2CID 23526646.
- ^ PMID 21561677.
- ^ PMID 25435979.
- ^ PMID 24350297.
- ^ S2CID 14765632.
- ^ PMID 26440212.
- ^ PMID 27506584.
Further reading
- Geyer M, Fackler OT, Peterlin BM (July 2001). "Structure--function relationships in HIV-1 Nef". EMBO Reports. 2 (7): 580–585. PMID 11463741.
- Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M (April 2003). "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". Journal of Biosciences. 28 (3): 323–335. S2CID 33749514.
- Bénichou S, Benmerah A (January 2003). "[The HIV nef and the Kaposi-sarcoma-associated virus K3/K5 proteins: "parasites"of the endocytosis pathway]". Médecine/Sciences. 19 (1): 100–106. PMID 12836198.
- Leavitt SA, SchOn A, Klein JC, Manjappara U, Chaiken IM, Freire E (February 2004). "Interactions of HIV-1 proteins gp120 and Nef with cellular partners define a novel allosteric paradigm". Current Protein & Peptide Science. 5 (1): 1–8. PMID 14965316.
- Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M (April 2004). "HIV/SIV escape from immune surveillance: focus on Nef". Current HIV Research. 2 (2): 141–151. PMID 15078178.
- Joseph AM, Kumar M, Mitra D (January 2005). "Nef: "necessary and enforcing factor" in HIV infection". Current HIV Research. 3 (1): 87–94. PMID 15638726.
- Anderson JL, Hope TJ (April 2004). "HIV accessory proteins and surviving the host cell". Current HIV/AIDS Reports. 1 (1): 47–53. S2CID 34731265.
- Kozlowski S, Corr M, Takeshita T, Boyd LF, Pendleton CD, Germain RN, et al. (June 1992). "Serum angiotensin-1 converting enzyme activity processes a human immunodeficiency virus 1 gp160 peptide for presentation by major histocompatibility complex class I molecules". The Journal of Experimental Medicine. 175 (6): 1417–1422. PMID 1316930.
- Lury D, Epstein H, Holmes N (1991). "The human class I MHC gene HLA-F is expressed in lymphocytes". International Immunology. 2 (6): 531–537. PMID 1707659.
- Takahashi H, Merli S, Putney SD, Houghten R, Moss B, Germain RN, Berzofsky JA (October 1989). "A single amino acid interchange yields reciprocal CTL specificities for HIV-1 gp160". Science. 246 (4926): 118–121. PMID 2789433.
- Dianzani U, Bragardo M, Buonfiglio D, Redoglia V, Funaro A, Portoles P, et al. (May 1995). "Modulation of CD4 lateral interaction with lymphocyte surface molecules induced by HIV-1 gp120". European Journal of Immunology. 25 (5): 1306–1311. S2CID 37717142.
- Howcroft TK, Palmer LA, Brown J, Rellahan B, Kashanchi F, Brady JN, Singer DS (July 1995). "HIV Tat represses transcription through Sp1-like elements in the basal promoter". Immunity. 3 (1): 127–138. PMID 7621073.
- Chen YH, Böck G, Vornhagen R, Steindl F, Katinger H, Dierich MP (July 1994). "HIV-1 gp41 enhances major histocompatibility complex class I and ICAM-1 expression on H9 and U937 cells". International Archives of Allergy and Immunology. 104 (3): 227–231. PMID 7913356.
- Chen YH, Böck G, Vornhagen R, Steindl F, Katinger H, Dierich MP (September 1994). "HIV-1 gp41 binding proteins and antibodies to gp41 could inhibit enhancement of human Raji cell MHC class I and II expression by gp41". Molecular Immunology. 31 (13): 977–982. PMID 8084338.
- Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. PMID 8125298.
- Howcroft TK, Strebel K, Martin MA, Singer DS (May 1993). "Repression of MHC class I gene promoter activity by two-exon Tat of HIV". Science. 260 (5112): 1320–1322. PMID 8493575.
- Gasparini P, Borgato L, Piperno A, Girelli D, Olivieri O, Gottardi E, et al. (May 1993). "Linkage analysis of 6p21 polymorphic markers and the hereditary hemochromatosis: localization of the gene centromeric to HLA-F". Human Molecular Genetics. 2 (5): 571–576. PMID 8518796.
- Schwartz O, Maréchal V, Le Gall S, Lemonnier F, Heard JM (March 1996). "Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein". Nature Medicine. 2 (3): 338–342. S2CID 7461342.
- Alexander-Miller MA, Parker KC, Tsukui T, Pendleton CD, Coligan JE, Berzofsky JA (May 1996). "Molecular analysis of presentation by HLA-A2.1 of a promiscuously binding V3 loop peptide from the HIV-envelope protein to human cytotoxic T lymphocytes". International Immunology. 8 (5): 641–649. PMID 8671651.