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Review
HLA-G (major histocompatibility complex, class I, G)
Shang-Mian Yie
The Second Medical College/Teaching Hospital, Chengdu University of Traditional Chinese Medicine,
Chengdu, Sichuan, PR China (SMY)
Published in Atlas Database: January 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/HLAGID43744ch6p22.html
DOI: 10.4267/2042/47338
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
located approximately 1,2 kb from the ATG initiation
codon of the HLA-G gene. The CREB1 factor binds to
this region (-1380/-1370), as well as to two additional
cAMP response elements (CRE) dispersed through the
promoter region at positions -934 and -770 from the
ATG. An interferon-sensitive response element (ISRE)
is located at position -744 from the ATG (Lefebvre et
al., 2001). A heat shock element (HSE) is located
within the HLA-G promoter at position -459/-454 that
binds heat shock factor 1 (HSF-1) (Ibrahim et al.,
2000). A progesterone receptor response element
(PRE) is located at position -37 from the ATG (Yie et
al., 2006), and three ras response elements (RRES) are
situated along the HLA-G gene promoter (-1356, -142,
-53) (Flajollet et al., 2009).
The 3'-UTR of the HLA-G gene also exhibits several
regulatory elements including AU-rich motifs and a
poly-A signal to influence mRNA stability, turnover,
mobility and splicing pattern (Donadi et al., 2011).
The primary transcript of HLA-G can be spliced into 7
alternative mRNAs (figure 1D) that encode membranebound (HLA-G1, -G2, -G3, -G4) and soluble (HLAG5, -G6, -G7) protein isoforms (Carosella et al., 2003).
HLA-G1 is the full-length HLA-G molecule, HLA-G2
lacks exon 3, HLA-G3 lacks exons 3 and 4, and HLAG4 lacks exon 4. HLA-G1 to -G4 are membrane-bound
molecules due to the presence of the transmembrane
and cytoplasmic tail encoded by exons 5 and 6. HLAG5 is similar to HLA-G1 but retains intron 4, HLAG6 lacks exon 3 but retains intron 4, and HLA-G7
lacks exon 3 but retains intron 2. HLA-G5 and -G6 are
soluble forms due to the presence of intron 4, which
contains a premature stop codon to prevent the
translation of the transmembrane and cytoplasmic tail.
HLA-G7 is soluble due to the presence of intron 2,
which contains a premature stop codon.
Identity
Other names: MHC-G
HGNC (Hugo): HLA-G
Location: 6p22.1
DNA/RNA
Description
HLA-G is one of the non-classical class I (Ib) HLA
molecules. The HLA-G gene is located at the short arm
of chromosome 6 in the HLA region (6p21.2-21.3)
between HLA-A and HLA-F genes (figure 1A). The
gene structure of HLA-G is homologous to other HLA
class I (Ia) genes consisting of 7 introns and 8 exons
coding the heavy chain of the molecule. Exon 1
encodes the peptide signal, while exons 2, 3 and 4
encode the extracellular α1, α2 and α3 domains,
respectively. Exons 5 and 6 encode the transmembrane
and cytoplasmic domains of the heavy chain. Exon 7 is
always absent from mature mRNA and due to the stop
codon in exon 6; exon 8 is not translated (figure 1B).
Transcription
The functional mRNA level of a particular gene is
regulated by the rate of synthesis, mainly driven by the
promoter region (5'-UTR) of the given gene, as well as
by the rate of degradation, stability, localization and
translatability of the specific mRNA (Kuersten and
Goodwin, 2003). The HLA-G gene promoter has a
modified enhancer A (enhA), S and X1 sequence, and a
few alternative regulatory elements to regulate HLA-G
gene transcription (figure 1C). So far, these regulatory
elements include the locus control region (LCR)
(Schmidt et al., 1993; Yelavarthi et al., 1993), which is
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
403
HLA-G (major histocompatibility complex, class I, G)
Yie SM
Figure 1. The human leukocyte antigen-G (HLA-G) gene and transcription. A. HLA-G gene location. B. HLA-G gene structure
consisting of 7 introns (white color) and 8 exons (green color). C. HLA-G gene promoter exhibiting regulatory elements to regulate HLA-G
gene transcription and 3'-UTR of the HLA-G gene exhibiting several regulatory elements including AU-rich motifs and a Poly-A signal to
influence mRNA stability, turnover, mobility and splicing pattern. CRE stands for cAMP responsive element, RRES for ras response
elements, ISRE for interferon-sensitive response element, HSE for heat shock response element, PRE for progesterone response
element, and X1 for X1 box. D. HLA-G primary transcript can be spliced into 7 alternative mRNAs ranging from HLA-G1 to -G7.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
404
HLA-G (major histocompatibility complex, class I, G)
Yie SM
Figure 2. HLA-G protein and its function. A. HLA-G protein exhibits a heterodimer consisting of globular domains (α1, α2 and α3
domains, transmembrane and cytoplasmic domains) and a light chain (β2-microglobulin). B. Alternative splicing of the primary transcript
yields 7 protein isoforms: truncated isoforms are generated by excision of one or two exons encoding the globular domains, whereas
translation of intron 4 or intron 2 yields soluble isoforms that lack the transmembrane domain. HLA-G molecules can form homomultimers
through the generation of Cys42-Cys42 or Cys42-Cys147 disulphide bonds. C. Immunoregulatory activities mediated by HLA-G, where
the involved target cells and receptors are indicated.
The HLA-G7 isoform has only the α1 domain linked to
two amino acids encoded by intron 2, which is retained
in the corresponding transcript (Fujii et al., 1994;
Ishitani and Geraghty, 1992; Paul et al., 2000).
In addtion, HLA-G molecules can form dimers through
the creation of disulphide bonds between two unique
cysteine residues at positions 42 (Cys42-Cys42 bonds)
and 147 (Cys42-Cys147 bonds) of the HLA-G heavy
chain (figure 2B) (Boyson et al., 2002; Gonen-Gross et
al., 2003). The dimerization has an oblique orientation
that exposes the HLA-G receptor binding sites of the
α3 domain upwards, making them more accessible to
the receptors. Consequently, HLA-G dimers bind
receptors with higher affinity and slower dissociation
rates than monomers, and signal more efficiently than
monomers as well (Shiroishi et al., 2006).
Protein
Description
The HLA-G protein exhibits a heterodimer consisting
of globular domains (α1, α2 and α3 domains,
transmembrane and cytoplasmic domains) and a light
chain (β2-microglobulin) called monomer (figure 2A).
However, there may be 7 protein isoforms, generated
by alternative splicing of the primary transcript: four of
them being membrane-bound (HLA-G1, -G2, -G3 and G4) and three soluble (HLA-G5, -G6 and -G7) (figure
2B). HLA-G1 is the complete isoform associated with
β2-microglobulin. The HLA-G2 isoform has no α2
domain, while HLA-G3 has no α2 and α3 domains, and
HLA-G4 has no α3 domain. The soluble HLA-G5 and G6 isoforms contain the same extra globular domains
as HLA-G1 and -G2, respectively, generated by
transcripts conserving intron 4, which blocks the
translation of the transmembrane domain. The 5'-region
of intron 4 is translated until the generation of a stop
codon, which gives the HLA-G5 and -G6 isoforms a
tail of 21 amino acids responsible for their solubility.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
Expression
Classical class Ia antigens are ubiquitously expressed,
whereas the expression of HLA-G is restrictive. HLAG protein expression is only found in trophoblast cells
in the placenta, certain immune cells (in most cases
monocytes), thymus, cornea, proximal nail matrix,
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HLA-G (major histocompatibility complex, class I, G)
Yie SM
KIRs are transmembrane glycoproteins expressed by
natural killer cells and subsets of T cells, exhibiting two
(KIR2D)
or
three
(KIR3D)
extracellular
immunoglobulin-like domains, which also contain
ITIMs. The KIR2DL4 binds to the α1 domain of the
HLA-G molecule (Yan and Fan, 2005). However, the
binding site of KIR2DL4 to HLA-G remains unknown
(Donadi et al., 2011). Moreover, since an array of
activator and inhibitor receptors is expressed on the
surface of most NK cells and macrophages, and the
final effector function is dependent on the balance
between activator and inhibitor receptors (Hsu et al.,
2002), the role of the interaction between KIR2DL4
and HLA-G in the modulation of the immune response
has been a matter of much debate (LeMaoult et al.,
2003; Apps et al., 2008).
HLA-G has an inhibitory effect on cytotoxic cells
exhibiting CD8 on their surface through the interaction
of the α3 domain of HLA-G with the CD8 α/α
molecule. The α3 domain of HLA-G is the same site of
interaction with CD8 α/α and LILRBs. Even though the
CD8 α/α and LILIRBs binding sites overlap, LILIRBs
inhibit the binding of CD8 α/α to HLA molecules by
displacing CD8 α/α and activating ITIMs (Shiroishi et
al., 2003).
Beside the extracellular domains of HLA-G, all
segments of the molecule may contribute to its
function. The short cytoplasmic tail retains HLA-G
longer in the endoplasmic reticulum and prolongs the
half-life of the molecule on the cell surface because of
the lack of an endocytosis motif (Park et al., 2001; Park
and Ahn, 2003). This permits multiple interactions with
cells of the immune system.
Soluble HLA-G molecule can induce apoptosis in
CD8+ activated T lymphocytes as well as in CD8+ NK
cells (lacking the T cell receptor) at similar rates. The
binding of soluble HLA molecules to CD8 leads to
apoptosis upregulating Fas production and Fas/FasL
interaction (Puppo et al., 2002; Contini et al., 2003).
This
mechanism
represents
an
additional
immunomodulatory effect of HLA-G.
erythroblasts and mesenchymal stem cells (Kovats et
al., 1990; Crisa et al., 1997; Lila et al., 2001; Ishitani et
al., 2003; Rebmann et al., 2003; Morandi et al., 2008).
The reasons for HLA-G expression in some but not
other tissues have not been fully elucidated. However,
soluble HLA-G (sHLA-G) can be detected in the
serum/plasma of both men and women. The main
source of sHLA-G in the blood of men and nonpregnant women is most likely monocytes. Both CD4+
and CD8+ T cells and B cells also seem to be able to
secrete HLA-G5 although to a lesser extent (Rebmann
et al., 2003). The presence or level of sHLA-G in
serum/plasma samples is associated with HLA-G
polymorphism (Rebmann et al., 2001; Hviid et al.,
2004a; Hviid et al., 2004b; Rizzo et al., 2005).
As mentioned earlier, HLA-G expression is mainly
controlled at the transcriptional level by a unique gene
promoter and at the post-transcriptional level by
alternative splicing, mRNA stability, translation and
protein transport to the cell surface. Many factors have
been described that can potentially affect
transcriptional and post-transcriptional mechanisms
responsible for HLA-G regulation (Moreau et al.,
2009).
Function
It has been demonstrated that HLA-G is an immune
tolerogenic molecule, which plays an important role in
the suppression of the immune responses (Carosella et
al., 2008) (figure 2C). The immune-inhibitory function
of HLA-G is realized by interacting with leukocyte
receptors including leukocyte immunoglobulin-like
receptor subfamily B member 1 (LILRB1) and member
2 (LILRB2), and killer cell immunoglobulin-like
receptor 2DL4 (KIR2DL4) (Shiroishi et al., 2006; Gao
et al., 2000).
LILRB1s are expressed on the surface of several
leukocytes, such as NK and lymphomononuclear cells,
while LILRB2s are primarily expressed on the surface
of a restricted set of cells, including monocytes and
dendritic cells (Brown et al., 2004). Both LILRB1 and
LILRB2 have several inhibitory motifs (ITIM)
receptors based on the immunoreceptor tyrosine in their
cytoplasmic tail, which inhibits signaling events
triggered by stimulatory receptors (Dietrich et al.,
2001). LILRB1 and LILRB2 both interact with
classical HLA class I molecules. However, their
binding with HLA-G presents three- to four-fold higher
affinity when compared to classical molecules
(Shiroishi et al., 2003). LILRB1 and LILRB2 also bind
to the α3 domain and β2-microglobulin of the HLA-G
molecule, although LILRB2 binds with higher affinity
than LILRB1. LILRB2 binds more to the α3 domain
than to the β2-microglobulin domain. The binding sites
of LILRB1 and LILRB2 are distinct. The Tyr36 and
Arg38 residues of LILRB2 bind to the 195-197 loop of
the α3 domain of HLA-G, whereas the Tyr38 and
Tyr76 residues of LILRB1 bind to the Phe195 of HLAG (Shiroishi et al., 2006).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
Mutations
Somatic
44 HLA-G coding alleles have been defined based
upon 72 single nucleotide polymorphisms (SNP)
observed between exon 1 and intron 6. Nucleotide
variability in the coding region of the HLA-G gene is
evenly distributed throughout exons 2, 3 and 4, as well
as in introns (Donadi et al., 2011). The heavy chain
encoding region exhibits 33 SNPs but only 13 amino
acid variations are observed, 4 of them in α1, 6 in α2
and 3 in the α3 domain (Donadi et al., 2011). The
amino acid substitutions may account for the biological
function of HLA-G, including peptide binding, isoform
production, and ability to polymerize and modulate
immune system cells.
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HLA-G (major histocompatibility complex, class I, G)
Yie SM
The HLA-G promoter exhibits 29 SNPs to date. Since
many of these polymorphisms either coincide with or
are closed to the known regulatory elements, they may
affect the binding of the corresponding regulatory
factors (Tan et al., 2005; Hviid et al., 2006; Hviid et al.,
2004a; Hviid et al., 2004b). Polymorphisms located at
CpG sites may affect promoter methylation (Ober et al.,
2006).
In some cases, polymorphism in the promoter region
may be in linkage disequilibrium with 3'-UTR variants
(Nicolae et al., 2005), and some of them could
influence alternative splicing (Auboeuf et al., 2002)
and mRNA stability (Rousseau et al., 2003).
In contrast to the coding region, the 3'-UTR of the
HLA-G locus presents a high degree of variation. Since
the 3'-UTR of HLA-G gene exhibits several regulatory
elements including AU-rich motifs, a poly-A signal, as
well as signals that regulate the spatial and temporal
expression of an mRNA, the polymorphic sites may
influence mRNA stability, turnover, mobility and
splicing pattern. The polymorphic sites at the 3'-UTR
seem to bear ranged in several haplotypes (Alvarez et
al., 2009; Castelli et al., 2010; Donadi et al., 2011),
their influence seems to occur simultaneously.
Figure 3. The role of HLA-G in tumor immunoediting. HLA-G is involved in every phase of tumor immunoediting to inhibit host
immune response. During the tumor immunoediting process, HLA-G can be activated and up-regulated by many factors. Aberrant
expression of HLA-G can: 1) disable effectors of innate and adaptive immunity in the elimination phase; 2) alter antigen presentation and
contribute less immunogenic phenotype in the equilibrium phase; and 3) induce immunosuppressive cytokines and peripheral tolerance
to the tumor (plus processes described in the two previous phases) in the escape phase.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
407
HLA-G (major histocompatibility complex, class I, G)
Yie SM
(Yu and Fu, 2006). Also, it has been documented that
HLA-G can increase regulatory T cells within TILs in
breast and hepatocellular cancers (Chen et al., 2010;
Cai et al., 2009). The regulatory T cells are a subset of
immune T cells that inhibit the anti-tumor functions of
tumor-specific T cells (Shevach, 2002). Therefore,
current data suggest that the estimation of HLA-G
expression is a novel prognostic marker useful in
assessing host immune response since cancer can be
explained, at least in part, as an abnormal immune
system tolerance to uncontrolled cells (de la CruzMerino et al., 2008).
Furthermore, serum soluble HLA-G is increased in
various types of cancer patients (Pistoia et al., 2007;
Yie and Hu, 2011) including patients with melanoma
(Ugurel et al., 2001), acute leukemia (Gros et al.,
2006), multiple myeloma (Leleu et al., 2005),
neuroblastoma
(Morandi
et
al.,
2007),
lymphoproliferative disorders (Sebti et al., 2007),
breast or ovarian cancer (Singer et al., 2003; Chen et
al., 2010; He et al., 2010), non-small cell lung cancer
(Cao et al., 2011), esophageal cancer (Cao et al., 2011),
colorectal cancer (Zhu et al., 2011; Cao et al., 2011),
gastric cancer (Cao et al., 2011) and hepatocellular
carcinoma (Wang et al., 2011), when compared to
normal healthy controls or benign disease cases.
Although numerous and different cancer studies show
preferential up-regulation of HLA-G in advanced
diseases rather than in initial tumor lesions, currently
available HLA-G data do support the notion that HLAG can be used as a potential biomarker in the diagnosis
of human carcinomas (Yie and Hu, 2011).
Implicated in
Various cancers
Disease
Cancer is essentially considered a complex cell disease
caused by abnormalities in the genetic material of
transformed cells. However, cancer development is a
complicated progressive process that involves a
sequence of gene-environment interactions with
dysfunctions in multiple systems, including immune
functions. The immune system can specifically identify
and eliminate tumor cells based on their expression of
tumor-specific antigens or molecules induced during
malignant cell transformation. This process is referred
to as tumor immune surveillance (Swann and Smyth,
2007). Despite tumor immune surveillance, tumors can
still develop in the presence of a functioning immune
system. This occurs through tumor immunoediting, a
process that comprises three major phases (Urosevic
and Dummer, 2008): 1) the elimination phase in which
most immuno-genic tumor cells are eliminated by
cytotoxic T and NK cells; 2) the equilibrium phase in
which tumor cells with reduced immunogenicity are
selected; and 3) the escape phase in which variants that
no longer respond to the host immune system are
maintained (Urosevic and Dummer, 2008). HLA-G is
involved in every phase of tumor immunoediting by
decreasing the elimination of tumor cells, by inhibiting
the cytotoxic function of T and NK cells, and by
trogocytosis, (i.e. the intercell transference of viable
HLA-G molecules), which renders competent cytotoxic
cells unresponsive to tumor antigens (LeMaoult et al.,
2007; Caumartin et al., 2007) (figure 3).
Prognosis
HLA-G is aberrantly expressed in many human solid
malignant tumors in situ and malignant hematopoietic
diseases including breast, ovarian, clear renal cell,
colorectal, gastric, esophageal, lung, and hepatocellular
cancers, as well as acute myeloid leukaemia and
chronic lymphocytic leukemia (B-CLL) (Carosella et
al., 2008; Yie and Hu, 2011). The aberrant expression
of HLA-G in malignant neoplasm is significantly
correlated with poor clinical outcome of patients with
colorectal cancer (CRC) (Ye et al., 2007), gastric
cancer (GC) (Yie et al., 2007b), non-small cell lung
cancer (NSCLC) (Yie et al., 2007c), esophageal
squamous cell cancer (ESCC) (Yie et al., 2007a), breast
cancer (He et al., 2010), hepatocellular cancers (Cai et
al., 2009), and B-CLL (Nückel et al., 2005). This is due
to the fact that HLA-G expression favors tumor
development and metastasis in every phase of cancer
immunoediting by impairing anti-tumor immune
responses (Urosevic and Dummer, 2008).
A reverse correlation between HLA-G expression in
tumors and the degree of tumor-infiltrating
lymphocytes (TILs) has been demonstrated in a variety
of cancer types (Yie and Hu, 2011). The presence of
TILs indicates an anti-tumor cellular immune response
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
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This article should be referenced as such:
Yie SM, Hu Z. Human leukocyte antigen-G (HLA-G) as a
marker for diagnosis, prognosis and tumor immune escape in
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
Yie SM. HLA-G (major histocompatibility complex, class I, G).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6):403-411.
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