Tuning of NK-Specific HLA-C Expression by Alternative mRNA Splicing. 2019

Frederick J Goodson-Gregg, and Brian Rothbard, and Amy Zhang, and Paul W Wright, and Hongchuan Li, and Victoria E Walker-Sperling, and Mary Carrington, and Stephen K Anderson
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States.

A complex system regulating HLA-C expression in NK cells, driven by an NK-specific promoter that produces alternatively spliced variants of the 5'-UTR has been recently identified. Exon content of the NK-specific 5'-UTR varies strikingly across HLA-C alleles, with some exons being allele specific. In order to investigate the possibility that allelic variation in the 5'-UTR modulates HLA-C expression levels, cDNAs containing several distinct classes of 5'-UTR were compared. Subtle changes in 5'-UTR content had a significant effect on the expression of HLA-C*03 and HLA-C*12 cDNA clones, suggesting that alternative splicing can fine-tune the level of protein expression. The HLA-C*06 allele was found to be highly expressed in relation to the other alleles studied. However, its increased expression was primarily associated with differences in the peptide-binding groove. Although the impact of allele-specific alternative splicing of NK-Pro transcripts on protein levels can be modest when compared with the effect of changes in peptide-loading, alternative splicing may represent an additional regulatory mechanism to fine-tune HLA-C levels within NK cells in distinct tissue environments or at different stages of maturation in order to achieve optimal levels of missing-self recognition.

UI MeSH Term Description Entries
D007694 Killer Cells, Natural Bone marrow-derived lymphocytes that possess cytotoxic properties, classically directed against transformed and virus-infected cells. Unlike T CELLS; and B CELLS; NK CELLS are not antigen specific. The cytotoxicity of natural killer cells is determined by the collective signaling of an array of inhibitory and stimulatory CELL SURFACE RECEPTORS. A subset of T-LYMPHOCYTES referred to as NATURAL KILLER T CELLS shares some of the properties of this cell type. NK Cells,Natural Killer Cells,Cell, NK,Cell, Natural Killer,Cells, NK,Cells, Natural Killer,Killer Cell, Natural,NK Cell,Natural Killer Cell
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D005091 Exons The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA. Mini-Exon,Exon,Mini Exon,Mini-Exons
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000483 Alleles Variant forms of the same gene, occupying the same locus on homologous CHROMOSOMES, and governing the variants in production of the same gene product. Allelomorphs,Allele,Allelomorph
D012333 RNA, Messenger RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm. Messenger RNA,Messenger RNA, Polyadenylated,Poly(A) Tail,Poly(A)+ RNA,Poly(A)+ mRNA,RNA, Messenger, Polyadenylated,RNA, Polyadenylated,mRNA,mRNA, Non-Polyadenylated,mRNA, Polyadenylated,Non-Polyadenylated mRNA,Poly(A) RNA,Polyadenylated mRNA,Non Polyadenylated mRNA,Polyadenylated Messenger RNA,Polyadenylated RNA,RNA, Polyadenylated Messenger,mRNA, Non Polyadenylated
D015236 HLA-C Antigens Class I human histocompatibility (HLA) antigens encoded by a small cluster of structural genes at the C locus on chromosome 6. They have significantly lower immunogenicity than the HLA-A and -B determinants and are therefore of minor importance in donor/recipient crossmatching. Their primary role is their high-risk association with certain disease manifestations (e.g., spondylarthritis, psoriasis, multiple myeloma). Antigens, HLA-C,HLA-C,Antigens, HLA C,HLA C Antigens
D017398 Alternative Splicing A process whereby multiple RNA transcripts are generated from a single gene. Alternative splicing involves the splicing together of other possible sets of EXONS during the processing of some, but not all, transcripts of the gene. Thus a particular exon may be connected to any one of several alternative exons to form a mature RNA. The alternative forms of mature MESSENGER RNA produce PROTEIN ISOFORMS in which one part of the isoforms is common while the other parts are different. RNA Splicing, Alternative,Splicing, Alternative,Alternate Splicing,Nested Transcripts,Alternate Splicings,Alternative RNA Splicing,Alternative RNA Splicings,Alternative Splicings,Nested Transcript,RNA Splicings, Alternative,Splicing, Alternate,Splicing, Alternative RNA,Splicings, Alternate,Splicings, Alternative,Splicings, Alternative RNA,Transcript, Nested,Transcripts, Nested
D018076 DNA, Complementary Single-stranded complementary DNA synthesized from an RNA template by the action of RNA-dependent DNA polymerase. cDNA (i.e., complementary DNA, not circular DNA, not C-DNA) is used in a variety of molecular cloning experiments as well as serving as a specific hybridization probe. Complementary DNA,cDNA,cDNA Probes,Probes, cDNA
D020121 5' Untranslated Regions The sequence at the 5' end of the messenger RNA that does not code for product. This sequence contains the ribosome binding site and other transcription and translation regulating sequences. 5'UTR,Leader Sequences, mRNA,Leader mRNA Sequences,mRNA Leader Sequences,5' UTR,5' UTRs,5' Untranslated Region,5'UTRs,Leader Sequence, mRNA,Leader mRNA Sequence,Region, 5' Untranslated,Regions, 5' Untranslated,Sequence, Leader mRNA,Sequence, mRNA Leader,Sequences, Leader mRNA,Sequences, mRNA Leader,UTR, 5',UTRs, 5',Untranslated Region, 5',Untranslated Regions, 5',mRNA Leader Sequence,mRNA Sequence, Leader,mRNA Sequences, Leader

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