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Discrete Cleavage Motifs of Constitutive and Immunoproteasomes Revealed by Quantitative Analysis of Cleavage Products

Discrete Cleavage Motifs of Constitutive and Immunoproteasomes Revealed by Quantitative Analysis... Proteasomes are the main proteases responsible for cytosolic protein degradation and the production of major histocompatibility complex class I ligands. Incorporation of the interferon γ–inducible subunits low molecular weight protein (LMP)-2, LMP-7, and multicatalytic endopeptidase complex–like (MECL)-1 leads to the formation of immunoproteasomes which have been associated with more efficient class I antigen processing. Although differences in cleavage specificities of constitutive and immunoproteasomes have been observed frequently, cleavage motifs have not been described previously. We now report that cells expressing immunoproteasomes display a different peptide repertoire changing the overall cytotoxic T cell–specificity as indicated by the observation that LMP-7 −/− mice react against cells of LMP-7 wild-type mice. Moreover, using the 436 amino acid protein enolase-1 as an unmodified model substrate in combination with a quantitative approach, we analyzed a large collection of peptides generated by either set of proteasomes. Inspection of the amino acids flanking proteasomal cleavage sites allowed the description of two different cleavage motifs. These motifs finally explain recent findings describing differential processing of epitopes by constitutive and immunoproteasomes and are important to the understanding of peripheral T cell tolerization/activation as well as for effective vaccine development. constitutive proteasomes immunoproteasomes CTL epitope peptide repertoire tolerance Footnotes Abbreviations used in this paper: ChT, chymotrypsin; LCMV, lymphocytic choriomeningitis virus; LMP, low molecular weight protein; MALDI, matrix-assisted laser desorption ionization; MECL, multicatalytic endopeptidase complex–like; MS, mass spectrometry; NP, nucleoprotein; PGPH, peptidyl-glutamylpeptide-hydrolyzing; TAP, transporter-associated with antigen processing. R.E.M. Toes and A.K. Nussbaum contributed equally to this work. Submitted: 29 March 2001 Revision requested 10 May 2001 Accepted: 11 May 2001 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Experimental Medicine Rockefeller University Press

Discrete Cleavage Motifs of Constitutive and Immunoproteasomes Revealed by Quantitative Analysis of Cleavage Products

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Publisher
Rockefeller University Press
Copyright
© 2001 The Rockefeller University Press
ISSN
0022-1007
eISSN
1540-9538
DOI
10.1084/jem.194.1.1
Publisher site
See Article on Publisher Site

Abstract

Proteasomes are the main proteases responsible for cytosolic protein degradation and the production of major histocompatibility complex class I ligands. Incorporation of the interferon γ–inducible subunits low molecular weight protein (LMP)-2, LMP-7, and multicatalytic endopeptidase complex–like (MECL)-1 leads to the formation of immunoproteasomes which have been associated with more efficient class I antigen processing. Although differences in cleavage specificities of constitutive and immunoproteasomes have been observed frequently, cleavage motifs have not been described previously. We now report that cells expressing immunoproteasomes display a different peptide repertoire changing the overall cytotoxic T cell–specificity as indicated by the observation that LMP-7 −/− mice react against cells of LMP-7 wild-type mice. Moreover, using the 436 amino acid protein enolase-1 as an unmodified model substrate in combination with a quantitative approach, we analyzed a large collection of peptides generated by either set of proteasomes. Inspection of the amino acids flanking proteasomal cleavage sites allowed the description of two different cleavage motifs. These motifs finally explain recent findings describing differential processing of epitopes by constitutive and immunoproteasomes and are important to the understanding of peripheral T cell tolerization/activation as well as for effective vaccine development. constitutive proteasomes immunoproteasomes CTL epitope peptide repertoire tolerance Footnotes Abbreviations used in this paper: ChT, chymotrypsin; LCMV, lymphocytic choriomeningitis virus; LMP, low molecular weight protein; MALDI, matrix-assisted laser desorption ionization; MECL, multicatalytic endopeptidase complex–like; MS, mass spectrometry; NP, nucleoprotein; PGPH, peptidyl-glutamylpeptide-hydrolyzing; TAP, transporter-associated with antigen processing. R.E.M. Toes and A.K. Nussbaum contributed equally to this work. Submitted: 29 March 2001 Revision requested 10 May 2001 Accepted: 11 May 2001

Journal

The Journal of Experimental Medicine – Rockefeller University Press

Published: Jul 2, 2001

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