Overexpression of the proteasome subunits LMP2, LMP7, and MECL-1, but not PA28 alpha/beta, enhances the presentation of an immunodominant lymphocytic choriomeningitis virus T cell epitope

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Item Type:	Article
Title:	Overexpression of the proteasome subunits LMP2, LMP7, and MECL-1, but not PA28 alpha/beta, enhances the presentation of an immunodominant lymphocytic choriomeningitis virus T cell epitope
Creators Name:	Schwarz, K., van den Broek, M., Kostka, S., Kraft, R., Soza, A., Schmidtke, G., Kloetzel, P.M. and Groettrup, M.
Abstract:	The proteasome is a large protease complex that generates most of the peptide ligands of MHC class I molecules either in their final form or in the form of N-terminally extended precursors. Upon the stimulation of cells with IFN-γ, three constitutively expressed subunits of the 20S proteasome are replaced by the inducible subunits LMP2 (low-molecular mass polypeptide 2), LMP7, and MECL-1 (multicatalytic endopeptidase complex-like-1) to form so- called immunoproteasomes. We show in this study that overexpression of these three subunits in triple transfectants led to a marked enhancement in the H- 2L(d)-restricted presentation of the immunodominant nonameric epitope NP118, which is derived from the nucleoprotein (NP) of lymphocytic choriomeningitis virus. Overexpression of the α and β subunits of the IFN-γ-inducible proteasome regulator PA28, in contrast, did not have a comparable effect. In vitro, immunoproteasomes as compared with constitutive proteasomes generated higher amounts of 11- and 12-mer fragments containing the NP118 epitope. These are likely to be cytosolic precursors of NP118, as a proline anchor residue in the second position of NP118 may interfere with TAP-mediated transport of the nonameric epitope itself. In conclusion, we provide evidence that up-regulation of the three inducible subunits, LMP2, LMP7, and MECL-1, can result in a marked improvement of Ag presentation and that, depending on the epitope, PA28 and immunoproteasomes may differentially affect Ag processing.
Keywords:	Amino Acid Sequence, Antigen Presentation, Autoantigens, Cell Line, Cysteine Endopeptidases, Cytosol, H-2 Antigens, Hybridomas, Immunodominant Epitopes, Immunologic Adjuvants, Inbred BALB C Mice, Lymphocytic choriomeningitis virus, Molecular Sequence Data, Multienzyme Complexes, Nucleoproteins, Peptide Fragments, Proteasome Endopeptidase Complex, Protein Biosynthesis, Protein Precursors, Proteins, T-Lymphocyte Epitopes, Transfection, Viral Proteins, Animals, Mice
Source:	Journal of Immunology
ISSN:	0022-1767
Publisher:	American Association of Immunologists
Volume:	165
Number:	2
Page Range:	768-778
Date:	15 July 2000
Official Publication:	http://www.jimmunol.org/cgi/content/abstract/165/2/768
PubMed:	View item in PubMed

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