MHC linked genes associated with apoptosis/programmed cell death.
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Animals↗
Biomedical subjects
J Trowsdale
Publications and source records attributed to J Trowsdale.
Disassembly of nuclear inclusions in the dividing cell--a novel insight into neurodegeneration.
Spinocerebellar ataxias and Huntington's disease are examples of neurodegenerative diseases caused by a trinucleotide repeat expansion. One hallmark of such diseases is the formation of inclusion bodies (IBs) within neuronal tissue. Although these inclusions may play a pivotal role in the disease process, the reasons underlying their specific accumulation remain obscure. By studying intranuclear IBs in dividing cells we demonstrate for the first time that inclusions such as those of ataxin-1 disperse during mitosis, thus reducing the nuclear aggregate burden. IBs reform in the interphase nucleus. By high-resolution confocal microscopy we also show that inclusions comprise ordered structures capable of homotypic interactions. Unlike those of a non-pathologic protein, ataxin-1 inclusions were shown to be capable of non-specific protein sequestration. Our studies indicate that the specific accumulation of inclusions in terminally differentiated cells such as neurons is a direct consequence of their inability to divide and therefore provides a key to explaining their persistence in neurodegenerative disease.
Amino Acid Sequence↗
Sequence organisation of the class II region of the human MHC.
We present the genomic organisation of the extended class II region of the human MHC. This initial sequence, which is nearing completion, spans about 1.2 Mbp and is at present a composite of more than one haplotype. The sequencing of single haplotypes is planned for the future. The current sequence encompasses all of the known class II genes at the DP, DO, DM, DQ and DR loci as well as the transporter associated with antigen processing (TAP)/low molecular weight protein (LMP) antigen processing genes and the Tapasin locus, at the extended centromeric end.
Animals↗
Genetics and molecular genetics of the MHC.
The MHC is a well-characterised region of the human genome, containing a high diversity of genes and an apparent clustering of genes involved in the immune response. The genomic sequence of an 8 Mb section, containing the MHC and flanking regions and covering over 300 genes, will soon be available. Since this is a highly polymorphic region, the molecular genetics of the MHC and its relationship with disease have been studied in considerable detail.
Animals↗
Large-scale sequence comparisons reveal unusually high levels of variation in the HLA-DQB1 locus in the class II region of the human MHC.
Comparison of genomic sequences flanking the HLA-DQB1 locus in the human MHC class II region reveals local sequence variation of up to 10%, which is the highest level of sequence variation found in the human genome so far. The variation is haplotype-specific and extends far beyond the transcriptional unit of the DQB1 gene, suggesting hitch-hiking along with functionally selected alleles as the most likely mechanism. All major insertions/deletions (indels) were found to be of retroviral origin and in the immediate upstream region of DQB1. Possible cis-acting effects of these indels on the transcriptional regulation of DQB1 are discussed.
Ataxin-1↗
Antigen presentation: coming out gracefully.
Efficient assembly of antigen-presenting class I MHC molecules requires the formation of a complex between the class I molecule and the TAP peptide transporter. The complex has been found to contain an additional four proteins, which help to ensure optimal peptide loading onto the class I molecules.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Genomic structure and domain organisation of the human Bak gene.
The Bcl-2 homologue, Bak, is a potent inducer of apoptosis. FISH data presented here located the gene to 6p21.3. Mapping was consistent with its location centromeric of the HSET locus and approximately 400kb from the MHC. The construction of a contig of genomic clones across the locus facilitated the sequencing of a PAC containing the gene. Comparison of the gene structure to functional and physical domains revealed a good agreement between the physical structure and the intron-exon organisation. The position of a single intron was conserved in comparison to other members of the Bcl-2 family, namely Bax, CED-9, Bcl-X and Bcl-2, but all other introns were displaced, consistent with a divergent phylogeny.
Amino Acid Sequence↗
Sequence analysis of a 62-kb region overlapping the human KLRC cluster of genes.
The NKG2 family of genes (HGMW-approved symbol KLRC) contains at least four members (NKG2-A, -C, -E, and -F) which are localized to human chromosome 12p12.3-p13.2. This region, called the natural killer (NK) complex, encodes for lectin-like genes preferentially expressed on NK cells. One of them, the human CD94 gene (HGMW-approved symbol KLRD1), encodes for a protein that has been shown to be covalently associated with the NKG2-A molecule. In this report, we showed that the NKG2 and CD94 genes are localized in a small region (< 350 kb) and we mapped them in the following order: (NKG2-C/NKG2-A)/NKG2-E/NKG2-F/NKG2-D/CD 94. Sequence analysis of 62 kb spanning the NKG2-A, -E, -F, and -D loci allowed the identification of two LINE elements that could have been involved in the duplication of the NKG2 genes. Presence of one MIR and one L1ME2 element at homologous positions in the NKG2-A and NKG2-F genes is consistent with the existence of rodent NKG2 gene(s). Finally, we mapped the 5'-ends of the NKG2-A transcripts into two separate regions showing the existence of two separate transcriptional control regions upstream of the NKG2-A locus and defining putative promoter elements for these genes.
Antigens, CD↗
TAPASIN, DAXX, RGL2, HKE2 and four new genes (BING 1, 3 to 5) form a dense cluster at the centromeric end of the MHC.
TAPASIN, a gene recently shown to be required for antigen presentation through MHC class I molecules, is located 180 kbp centromeric of HLA-DP in a region linked to several diseases, and associated with altered developmental phenotypes in the mouse. We present the genomic analysis of a 70 kbp gene-dense segment flanking the TAPASIN locus, including sequence, structure and preliminary characterisation of seven additional genes. BING1 is a Zn finger gene containing a POZ motif. BING3 is similar to myosin regulatory light chain. BING4 shows homologies only to hypothetical yeast and Caenorhabditis elegans proteins. BING5 is found within an intron of BING4 on the complementary strand, and encodes a molecule with no homologies to database proteins. Another three genes were identified whose full sequence was not previously known; namely, RGL2, DAXX (BING2) and HKE2. RGL2 encodes an effector of Ras, homologous to the mouse RalGDS protein, Rlf. DAXX encodes an effector of Fas that stimulates apoptosis through the Jun kinase (JNK) pathway. The location of DAXX is of interest given the linkage of autoimmune disease to the MHC and to apoptosis.
Adaptor Proteins, Signal Transducing↗
Genomic analysis of the Tapasin gene, located close to the TAP loci in the MHC.
The Tapasin molecule is a member of the immunoglobulin (Ig) superfamily required for the association of TAP transporters and MHC class I heterodimers in the endoplasmic reticulum. In this study, the Tapasin gene was precisely mapped in relation to the MHC. The gene was centromeric of the HLA-DP locus between the HSET and HKE1.5 genes and within 500 kbp of the TAP1 and TAP2 genes. A homologous mouse EST was mapped to a syntenic position on chromosome 17, centromeric of the H-2 K locus. Similarly, the rat Tapasin gene was shown to be in an equivalent location with respect to the RT1.A locus. The localization of Tapasin, TAP, LMP and class I genes within such a short distance of each other on the chromosome implies some regulatory or functional significance. We determined the Tapasin gene sequence for comparison of its structure to that of other Ig superfamily members, such as MHC class I genes. The IgC domain was encoded by a separate exon. However, the positions of the other introns were not characteristic of other Ig superfamily genes, indicating that Tapasin has a distinct phylogeny.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
MHC class II-associated invariant chain peptide replacement by T cell epitopes: engineered invariant chain as a vehicle for directed and enhanced MHC class II antigen processing and presentation.
Proteolysis of the invariant chain (li) leads to the generation of abundant MHC class II-associated invariant chain peptides (CLIP), which bind in the MHC class II binding groove via supermotifs in a manner similar to that of antigenic peptides. We have engineered an li vector with the capacity to express any antigenic peptide of interest instead of CLIP, for T cell stimulation. When peripheral blood mononuclear cells (PBMC) were pulsed with li hybrids encoding T cell epitopes of tetanus toxin or acetylcholine receptor, stimulation of T cells was dramatically enhanced compared to stimulation after priming with either the native or recombinant proteins. Site-specific insertion of antigenic sequences into the CLIP region promoted enhanced antigenicity of li hybrids which were shown to be processed intracellularly in a chloroquine-sensitive compartment. Naturally processed T helper epitopes were visualized directly on the surface of PBMC and identified as analogs of CLIP associated with MHC class II molecules. This novel li vector provides a flexible and efficient system for the delivery of defined peptide epitopes to T cells which might be useful in the development of specific vaccines and in the study of intracellular processing.
Amino Acid Sequence↗
Isotypic variation of novel immunoglobulin-like transcript/killer cell inhibitory receptor loci in the leukocyte receptor complex.
The leukocyte receptor complex (LRC) on human chromosome 19q13.4 encompasses at least four families of related genes: immunoglobulin-like transcripts (ILT), killer cell inhibitory receptors (KIR), the leukocyte-associated inhibitory receptors (LAIR) and the Fcalpha receptor (Fc(alpha)R). We determined the genomic organization of a region of DNA spanning the junction of the ILT and KIR gene complexes. Extensive sequence data were collected for ILT3, two novel genes, ILT9 and ILT10, and one novel KIR locus (KIRCI). These loci, along with other reported sequences from the region, encoded a leader sequence split into two exons, upstream of two to four immunoglobulin (Ig) domains, each on a separate exon. Downstream of the Ig domains, however, the organization differs markedly between inhibitory and activating ILT. These data are consistent with a highly conserved gene arrangement for all superfamily members suggesting duplication of primordial sequences. ILT3 and KIRCI were in the same head-to-tail orientation as has been described for other KIR loci which may facilitate addition or loss of genes between different haplotypes.
Base Sequence↗
Heat shock proteins, HLA-DR and rheumatoid arthritis.
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Amino Acid Sequence↗
Physical map of human 6p21.2-6p21.3: region flanking the centromeric end of the major histocompatibility complex.
We have physically mapped and cloned a 2.5-Mb chromosomal segment flanking the centromeric end of the major histocompatibility complex (MHC). We characterized in detail 27 YACs, 144 cosmids, 51 PACs, and 5 BACs, which will facilitate the complete genomic sequencing of this region of chromosome 6. The contig contains the genes encoding CSBP, p21, HSU09564 serine kinase, ZNF76, TCP-11, RPS10, HMGI(Y), BAK, and the human homolog of Tctex-7 (HSET). The GLO1 gene was mapped further centromeric in the 6p21.2-6p21.1 region toward TCTE-1. The gene order of the GLO1-HMGI(Y) segment in respect to the centromere is similar to the gene order in the mouse t-chromosome distal inversion, indicating that there is conservation in gene content but not gene order between humans and mice in this region. The close linkage of the BAK and CSBP genes to the MHC is of interest because of their possible involvement in autoimmune disease.
Bacterial Proteins↗
HLA-DO is a negative modulator of HLA-DM-mediated MHC class II peptide loading.
BACKGROUND: Class II molecules of the major histocompatibility complex become loaded with antigenic peptides after dissociation of invariant chainderived peptides (CLIP) from the peptide-binding groove. The human leukocyte antigen (HLA)-DM is a prerequisite for this process, which takes place in specialised intracellular compartments. HLA-DM catalyses the peptide-exchange process, simultaneously functioning as a peptide 'editor', favouring the presentation of stably binding peptides. Recently, HLA-DO, an unconventional class II molecule, has been found associated with HLA-DM in B cells, yet its function has remained elusive. RESULTS: The function of the HLA-DO complex was investigated by expression of both chains of the HLA-DO heterodimer (either alone or fused to green fluorescent protein) in human Mel JuSo cells. Expression of HLA-DO resulted in greatly enhanced surface expression of CLIP via HLA-DR3, the conversion of class II complexes to the SDS-unstable phenotype and reduced antigen presentation to T-cell clones. Analysis of peptides eluted from HLA-DR3 demonstrated that CLIP was the major peptide bound to class II in the HLA-DO transfectants. Peptide exchange assays in vitro revealed that HLA-DO functions directly at the level of class II peptide loading by inhibiting the catalytic action of HLA-DM. CONCLUSIONS: HLA-DO is a negative modulator of HLA-DM. By stably associating with HLA-DM, the catalytic action of HLA-DM on class II peptide loading is inhibited. HLA-DO thus affects the peptide repertoire that is eventually presented to the immune system by MHC class II molecules.
Amino Acid Sequence↗
Interaction between HLA-DM and HLA-DR involves regions that undergo conformational changes at lysosomal pH.
Antigenic peptide loading of major histocompatibility complex class II molecules is enhanced by lysosomal pH and catalyzed by the HLA-DM molecule. The physical mechanism behind the catalytic activity of DM was investigated by using time-resolved fluorescence anisotropy (TRFA) and fluorescence binding studies with the dye 8-anilino-1-naphthalenesulfonic acid (ANS). We demonstrate that the conformations of both HLA-DM and HLA-DR3, irrespective of the composition of bound peptide, are pH sensitive. Both complexes reversibly expose more nonpolar regions upon protonation. Interaction of DM with DR shields these hydrophobic domains from the aqueous environment, leading to stabilization of the DM and DR conformations. At lysosomal pH, the uncovering of additional hydrophobic patches leads to a more extensive DM-DR association. We propose that DM catalyzes class II peptide loading by stabilizing the low-pH conformation of DR, favoring peptide exchange. The DM-DR association involves a larger hydrophobic surface area with DR/class II-associated invariant chain peptides (CLIP) than with stable DR/peptide complexes, explaining the preferred association of DM with the former. The data support a release mechanism of DM from the DM-DR complex through reduction of the interactive surface, upon binding of class II molecules with antigenic peptide or upon neutralization of the DM-DR complex at the cell surface.
Anilino Naphthalenesulfonates↗
Chromosomal localization, gene structure and transcription pattern of the ORFX gene, a homologue of the MHC-linked RING3 gene.
We have mapped the human ORFX gene to chromosome 9q34 and determined its complete gene structure. Comparison with RING3, the human MHC-linked homologue on 6p21.3, shows the two gene structures to be highly conserved but with an approximate threefold expansion in the ORFX introns. RING3 and ORFX are found to be ubiquitously expressed in human adult and foetal tissues. Evidence suggests that the two genes may have arisen from an ancient duplication in a common ancestral chromosome.
Adult↗
Genetic relationships of the genes encoding the human proteasome beta subunits and the proteasome PA28 complex.
Genomic clones were obtained for the genes encoding the beta subunits of the human proteasome and for the associated proteasome activators PA28alpha and beta (PSME1 and PSME2, respectively). Fluorescence in situ hybridization was used to map the gene encoding the beta subunit PSMB3 (beta3 hs, HsC10-II) to chromosome band 2q35, PSMB2 (beta4 hs, HsC7-I) to band 1p34.2, and PSMB4 (beta7 hs, HSBpros 26) to band 1q21. Genes encoding the alpha and beta subunits of the PA28 complex were found closely linked on chromosome band 14q11.2, within 1 Mb of the beta proteasome locus PSMB5 (beta5 hs, MB1, X). These data complete the mapping of the human proteasome beta subunit loci. With the exception of the genes encoding the PSMB9 and PSMB8 (LMP2 and LMP7, respectively) subunits, the beta genes were not closely linked in the human genome. Both PSMB2 and PSMB4 mapped to a region of chromosome 1 that is proposed to be paralogous to other regions of the human genome where beta proteasome genes map: chromosome 6 containing the major histocompatibility complex (MHC) and chromosome 9. The independent regulation of expression of all of these genes, implied by this study, is consistent with a key role for proteasome assembly in coordination of the complex.
Animals↗