Characterization of a Proteasome and TAP-independent Presentation of Intracellular Epitopes by HLA-B27 Molecules

Handle URI:
http://hdl.handle.net/10754/597756
Title:
Characterization of a Proteasome and TAP-independent Presentation of Intracellular Epitopes by HLA-B27 Molecules
Authors:
Magnacca, A.; Persiconi, I.; Nurzia, E.; Caristi, S.; Meloni, F.; Barnaba, V.; Paladini, F.; Raimondo, D.; Fiorillo, M. T.; Sorrentino, R.
Abstract:
Nascent HLA-class I molecules are stabilized by proteasome-derived peptides in the ER and the new complexes proceed to the cell surface through the post-ER vesicles. It has been shown, however, that less stable complexes can exchange peptides in the Trans Golgi Network (TGN). HLA-B27 are the most studied HLA-class I molecules due to their association with Ankylosing Spondylitis (AS). Chimeric proteins driven by TAT of HIV have been exploited by us to deliver viral epitopes, whose cross-presentation by the HLA-B27 molecules was proteasome and TAP-independent and not restricted to Antigen-Presenting Cells (APC). Here, using these chimeric proteins as epitope suppliers, we compared with each other and with the HLA-A2 molecules, the two HLA-B*2705 and B*2709 alleles differing at residue 116 (D116H) and differentially associated with AS. We found that the antigen presentation by the two HLA-B27 molecules was proteasome-, TAP-, and APC-independent whereas the presentation by the HLA-A2 molecules required proteasome, TAP and professional APC. Assuming that such difference could be due to the unpaired, highly reactive Cys-67 distinguishing the HLA-B27 molecules, C67S mutants in HLA-B*2705 and B*2709 and V67C mutant in HLA-A*0201 were also analyzed. The results showed that this mutation did not influence the HLA-A2-restricted antigen presentation while it drastically affected the HLA-B27-restricted presentation with, however, remarkable differences between B*2705 and B*2709. The data, together with the occurrence on the cell surface of unfolded molecules in the case of C67S-B*2705 mutant but not in that of C67S-B*2709 mutant, indicates that Cys-67 has a more critical role in stabilizing the B*2705 rather than the B*2709 complexes.
Citation:
Magnacca A, Persiconi I, Nurzia E, Caristi S, Meloni F, et al. (2012) Characterization of a Proteasome and TAP-independent Presentation of Intracellular Epitopes by HLA-B27 Molecules. Journal of Biological Chemistry 287: 30358–30367. Available: http://dx.doi.org/10.1074/jbc.M112.384339.
Publisher:
American Society for Biochemistry & Molecular Biology (ASBMB)
Journal:
Journal of Biological Chemistry
KAUST Grant Number:
KUK-11-012-43
Issue Date:
17-Jul-2012
DOI:
10.1074/jbc.M112.384339
PubMed ID:
22807446
PubMed Central ID:
PMC3436287
Type:
Article
ISSN:
0021-9258; 1083-351X
Sponsors:
This work was supported by the Italian Ministry of Education, University and Research (MIUR) through PRIN (grant no2008C33HRL-004), by the Istituto Pasteur-Fondazione Cenci Bolognetti, King Abdullah University of Science and Technology (KAUST) (Award No. KUK-11-012-43) Fondazione Roma and by Sapienza through Progetti di Ateneo (Grant noC26A10CT9F).
Appears in Collections:
Publications Acknowledging KAUST Support

Full metadata record

DC FieldValue Language
dc.contributor.authorMagnacca, A.en
dc.contributor.authorPersiconi, I.en
dc.contributor.authorNurzia, E.en
dc.contributor.authorCaristi, S.en
dc.contributor.authorMeloni, F.en
dc.contributor.authorBarnaba, V.en
dc.contributor.authorPaladini, F.en
dc.contributor.authorRaimondo, D.en
dc.contributor.authorFiorillo, M. T.en
dc.contributor.authorSorrentino, R.en
dc.date.accessioned2016-02-25T12:56:09Zen
dc.date.available2016-02-25T12:56:09Zen
dc.date.issued2012-07-17en
dc.identifier.citationMagnacca A, Persiconi I, Nurzia E, Caristi S, Meloni F, et al. (2012) Characterization of a Proteasome and TAP-independent Presentation of Intracellular Epitopes by HLA-B27 Molecules. Journal of Biological Chemistry 287: 30358–30367. Available: http://dx.doi.org/10.1074/jbc.M112.384339.en
dc.identifier.issn0021-9258en
dc.identifier.issn1083-351Xen
dc.identifier.pmid22807446en
dc.identifier.doi10.1074/jbc.M112.384339en
dc.identifier.urihttp://hdl.handle.net/10754/597756en
dc.description.abstractNascent HLA-class I molecules are stabilized by proteasome-derived peptides in the ER and the new complexes proceed to the cell surface through the post-ER vesicles. It has been shown, however, that less stable complexes can exchange peptides in the Trans Golgi Network (TGN). HLA-B27 are the most studied HLA-class I molecules due to their association with Ankylosing Spondylitis (AS). Chimeric proteins driven by TAT of HIV have been exploited by us to deliver viral epitopes, whose cross-presentation by the HLA-B27 molecules was proteasome and TAP-independent and not restricted to Antigen-Presenting Cells (APC). Here, using these chimeric proteins as epitope suppliers, we compared with each other and with the HLA-A2 molecules, the two HLA-B*2705 and B*2709 alleles differing at residue 116 (D116H) and differentially associated with AS. We found that the antigen presentation by the two HLA-B27 molecules was proteasome-, TAP-, and APC-independent whereas the presentation by the HLA-A2 molecules required proteasome, TAP and professional APC. Assuming that such difference could be due to the unpaired, highly reactive Cys-67 distinguishing the HLA-B27 molecules, C67S mutants in HLA-B*2705 and B*2709 and V67C mutant in HLA-A*0201 were also analyzed. The results showed that this mutation did not influence the HLA-A2-restricted antigen presentation while it drastically affected the HLA-B27-restricted presentation with, however, remarkable differences between B*2705 and B*2709. The data, together with the occurrence on the cell surface of unfolded molecules in the case of C67S-B*2705 mutant but not in that of C67S-B*2709 mutant, indicates that Cys-67 has a more critical role in stabilizing the B*2705 rather than the B*2709 complexes.en
dc.description.sponsorshipThis work was supported by the Italian Ministry of Education, University and Research (MIUR) through PRIN (grant no2008C33HRL-004), by the Istituto Pasteur-Fondazione Cenci Bolognetti, King Abdullah University of Science and Technology (KAUST) (Award No. KUK-11-012-43) Fondazione Roma and by Sapienza through Progetti di Ateneo (Grant noC26A10CT9F).en
dc.publisherAmerican Society for Biochemistry & Molecular Biology (ASBMB)en
dc.titleCharacterization of a Proteasome and TAP-independent Presentation of Intracellular Epitopes by HLA-B27 Moleculesen
dc.typeArticleen
dc.identifier.journalJournal of Biological Chemistryen
dc.identifier.pmcidPMC3436287en
dc.contributor.institutionUniversita degli Studi di Roma La Sapienza, Rome, Italyen
kaust.grant.numberKUK-11-012-43en

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