Eur. J. Immunol. 2015. 45: 3257-3268 IntroductionThe differentiation antigen melanoma antigen recognized by T cells/melanoma antigen A (thereafter named MART-1) has been a major target in antigen-specific immunotherapy of malignant melanoma and in particular its immunodominant HLA-A*0201-restricted CD8 + T-cell epitope MART-1 26(27)-35 [1,2]. But clinical efficacy of different MART-1-specific therapies has only been limited. In vitro studies employing high-affinity MART-1-specific CD8 + T-cell clones demonstrated that some melanoma cell lines, despite expression of MART-1 and the corresponding HLA allele, were only barely recognized by specific T cells [3]. While different variants of the MART-1 epitope (including the MART-1 [26][27][28][29][30][31][32][33][34][35] 10-mer and the MART-1 27-35 9-mer) have been identified, only the 9-mer epitope can be eluted in significant amounts from the cell surface of melanoma cells [4]. This suggests that mechanisms related to antigen processing interfere with efficient generation of the 10-mer MART-1 26-35 epitope in tumor cells. It has been demonstrated that MART-1 26-35 epitope processing is controlled by the proteasome, the major proteolytic machinery of the cytosol [5]. The standard proteasome (SP) contains the catalytic subunits β1, β2, and β5, whereas exposure of cells to IFN-γ enhances expression and incorporation of the immunosubunits β1i/LMP2 (LMP, low molecular weight protein), β2i/MECL-1 (multicatalytic endopeptidase complex-like 1), and β5i/LMP7 into nascent proteasome complexes. Immunosubunit-containing proteasomes represent catalytic properties that are different from that of SPs [6]. Interestingly, IFN-γ has been described to interfere with efficient MART-1 26-35 epitope generation due to the activity of the proteasome immunosubunits β1i/LMP2 and β5i/LMP7 [5,7,8].To degrade cellular proteins in an ubiquitin-dependent manner, 20S catalytic core particles are connected to 19S regulatory complexes. In the presence of IFN-γ, the expression of PA28α/β (PA, proteasome activator), an activator complex that in combination with the 19S regulatory complex and the 20S proteasome forms so-called PA28-20S-19S hybrid proteasome complexes, is induced [9,10]. The PA28 has been associated with positive effects on epitope processing due to facilitating the access of substrates to the active sites of the proteasome. Generation of the TRP2 360-368 epitope derived from the melanoma antigen tyrosinase-related protein 2 (TRP2) was shown to be completely dependent on PA28 activity by influencing the proteasomal structure and cleavage specificity [11]. Moreover, IFN-γ induces the expression of the ER-resident aminopeptidases ERAP1/2 that trim epitope precursor peptides released into the ER to bind MHC class I molecules [12][13][14][15]. In this context, increased epitope generation has been preferentially attributed to ERAP1, whereas the role of ERAP2 in epitope processing is still under debate [16]. Varying expression levels of ERAP1/2 have been described in different tumor enti...
The two major components of the acidic glycolipid fraction from the pupae of Calliphora vicina were isolated using high-performance liquid chromatography. The acidic moiety was identified as glucuronic acid by jglucuronidase cleavage and gas chromatographic analysis as the pentafluoropropionyl derivative. The structures of the carbohydrate moiety were elucidated by peracetylation, methylation, exoglycosidase cleavage, fast-atombombardment mass spectrometric and 'H-nuclear magnetic resonance spectroscopic analysis. The only difference between the two hexasaccharide variants was the presence, in one of them, of a phosphoethanolamine (AeP) sidechain on the third sugar of the sequence, i. e. N-acetylglucosamine. The composition of the ceramide moiety was dominated by a C2,, : fatty acid (arachidic acid) and a CI4 : sphingoid base (tetradecasphing-4-enine). The chemical structures of the two insect acidic glycosphingolipids were determined to be:Such glucuronic-acid-containing insect glycosphingolipids have been given the generic name arthrosides, with the implied synonymity to the gangliosides.Systematic structural elucidation of glycosphingolipids from members of the phyla Mollusca and Athropoda (class: Insecta) of the Invertebrata (Protostomia) have revealed major divergences in the carbohydrate moiety compared to those of the Vertebrata (Deuterostomia). The mollu series (Ml) of the Mollusca and arthro series (Ap) of the Arthropoda are characterised by a mactose-containing ceramide disaccharide in which the galactose residue of vertebrate lactose is replaced by mannose. Abbreviations. Gangliosides of the sialoganglio series are designated as was suggested previously [I] : GI,,I = I13NeuAc-LacCer, G,,,l = I13NeuAc-Gg,Cer. The shorthand abbreviations of glycosphingolipids (GSL) of the arthro series (Ap), characterized by the monosaccharide sequence of the arthroheptaose (Ap7) GlcNAcPl3GalP1 -3GalNAcal -4GalNAcP1 -4GlcNAcPI -3ManDl -4Glc, are N, Nz, A, and Az, where N stands for GSL with a neutral oligosaccharide chain, A for those with an additional acidic substituent (glucuronic acid); the lower case letter z is added for members that carry the zwitterionic substituent 2-aminoethylphosphate; arabic numerals 1-7 indicate the number of constituent neutral monosaccharides. In the case of two isomeric ceramide pentahexosides, a lower-case letter b or c distinguishes IV3Gala-Ap,Cer (N5b) and IV3GalP-Ap,Cer ( N~c ) , respectively. Mab, monoclonal antibody; Mac, mactose, i. e. Manp(1-4)Glc; FAB-MS, fast atom-bombardment mass spectrometry.Enzymes. P-Glucuronidase (EC 3.2.1.31), P-galactosidase (EC 3.2.1.23).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.