PubMed · 8566439
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A M Benham, J J Neefjes. 1995. Antigen processing by the class I pathway.. https://doi.org/10.1042/bst0230664
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The TAP1 and TAP2 proteins form a heterodimer that transports short peptides from the cytosol into the endoplasmic reticulum lumen. Extensive allelic polymorphism of the rat TAP transporter has been shown to affect the repertoire of peptides presented by MHC class I molecules. Structural polymorphism in the human TAP genes is much more limited and has not been observed to have functional consequences. We have examined the polymorphism in mouse TAP1 and TAP2 in inbred mice. While the number of polymorphic positions in these molecules is more similar to that in human than to that in the rat, all strains examined have a structurally unique TAP transporter, suggesting the possibility of functional polymorphism. Furthermore, allelic variations in the mouse transporter are predominantly located in or adjacent to membrane-spanning domains, although no significant bias in the ratio of nonsynonymous to synonymous substitutions is observed. We also report that mouse TAP1 begins 172 amino acids upstream of the previously published start site and report the genomic organization of mouse Tap-1 and Tap-2.
With recent studies suggesting a key role for professional antigen presenting cells in the induction of major histocompatibility class I cellular immune responses, we initiated studies on the regulation of Tap-1 and Tap-2 gene expression in macrophages. Stimulation of the human macrophage cell line THP-1 with interferon-gamma (IFN-gamma) resulted in maximal induction of both Tap-1 and Tap-2 mRNA within 24 hr. Nuclear run-on analyses showed that the increased expression of Tap-1 and Tap-2 was controlled at the level of transcription. Half-life studies demonstrated that mRNAs for both genes became destabilized after stimulation of THP-1 cells with IFN-gamma for 24 hr, suggesting that a posttranscriptional mechanism down-regulates TAP gene expression following activation. Treatment of cells with both IFN-gamma and lipopolysaccharide (LPS) altered the kinetics and amount of Tap-1 mRNA and protein expression, compared to those with stimulation with IFN-gamma alone. These data suggest that LPS enhances the ability of macrophages stimulated with IFN-gamma to initiate a cellular immune response by altering the kinetics of TAP gene expression.
The herpes simplex virus (HSV) immediate early protein ICP47 inhibits the transporter associated with antigen processing (TAP)-dependent peptide translocation. As a consequence, empty major histocompatibility complex (MHC) class I molecules are retained in the endoplasmic reticulum and recognition of HSV-infected cells by cytotoxic T lymphocytes is abolished. We chemically synthesized full-length ICP47 (sICP47) and show that sICP47 inhibits TAP-dependent peptide translocation in human cells. Its biological activity is indistinguishable from that of recombinant ICP47 (rICP47). By using synthetic peptides, we mapped the core sequence of ICP47 minimally required for TAP inhibition to residues 2-35. This segment is located within the region of the molecule conserved between ICP47 from HSV-1 and HSV-2. Through alanine scanning substitution we identified three segments within this region that are critical for the ability to inhibit TAP function. The interaction of ICP47 with TAP is unlikely to mimic precisely that of the transported peptides, as deduced from differential labeling of the TAP1 and TAP2 subunits using sICP47 fragments with chemical cross-linkers.