Exon 5 encoding the transmembrane region of HLA-A contains a transitional region for the induction of nonsense-mediated mRNA decay.
HLA class I alleles containing premature termination codons (PTCs) are increasingly being found. To understand their effects on MHC class I expression, HLA-A*2402 mutants containing PTCs were transfected into class I-deficient cells, and expression of HLA-A mRNA and protein was determined. In exons 2, 3, and 4, and in the 5' part of exon 5, PTCs reduced mRNA levels by up to 90%, whereas in the 3' part of exon 5 and in exons 6 and 7 they had little effect. Transition in the extent of nonsense-mediated mRNA decay occurred within a 48-nt segment of exon 5, placed 58 nt upstream from the exon 5/exon 6 junction. This transition did not conform to the positional rule obeyed by other genes, which predicted it to be approximately 50-55 nt upstream of the exon 7/exon 8 junction and thus placing it in exon 6. Mutants containing extra gene segments showed the difference is caused by the small size of exons 5 and 6, which renders them invisible to the surveillance machinery. For the protein, a transition from secretion to membrane association occurs within a 26-nt segment of exon 5, 17 nt upstream of the exon 5/exon 6 junction. Premature termination in exon 5 can produce secreted and membrane-associated HLA-A variants expressed at high levels.
Watanabe
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Y
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Magor
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KE
Parham
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P
D000595:Amino Acid Sequence; D002461:Cell Line, Transformed; D018389:Codon, Nonsense; D015536:Down-Regulation; D005091:Exons; D015234:HLA-A Antigens / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection
D018389:Codon, Nonsense; D015234:HLA-A Antigens; D012333:RNA, Messenger