Two new proteases in the MHC class I processing pathway

The proteasome generates exact major histocompatibility complex (MHC) class I ligands as well as NH2-terminal-extended precursor peptides. The proteases responsible for the final NH2-terminal trimming of the precursor peptides had, until now, not been determined. By using specific selective criteria we purified two cytosolic proteolytic activities, puromycin-sensitive aminopeptidase and bleomycin hydrolase. These proteases could remove NH2-terminal amino acids from the vesicular stomatitis virus nucleoprotein cytotoxic T cell epitope 52–59 (RGYVYQGL) resulting, in combination with proteasomes, in the generation of the correct epitope. Our data provide evidence for the existence of redundant systems acting downstream of the proteasome in the antigen-processing pathway for MHC class I molecules.

[1]  C. López-Otín,et al.  Gene Characterization, Promoter Analysis, and Chromosomal Localization of Human Bleomycin Hydrolase* , 1997, The Journal of Biological Chemistry.

[2]  P. Paz,et al.  Discrete proteolytic intermediates in the MHC class I antigen processing pathway and MHC I-dependent peptide trimming in the ER. , 1999, Immunity.

[3]  Hans-Georg Rammensee,et al.  Cellular peptide composition governed by major histocompatibility complex class I molecules , 1990, Nature.

[4]  W. Baumeister,et al.  A giant protease with potential to substitute for some functions of the proteasome. , 1999, Science.

[5]  J. Schwartz,et al.  Characterization and inhibition of a cholecystokinin-inactivating serine peptidase , 1996, Nature.

[6]  L. Hersh,et al.  Cloning and analysis of the gene for the human puromycin-sensitive aminopeptidase. , 1999, Biochemical and biophysical research communications.

[7]  S. Tonegawa,et al.  Altered peptidase and viral-specific T cell response in LMP2 mutant mice. , 1994, Immunity.

[8]  L. Joshua-Tor,et al.  Crystal structure of human bleomycin hydrolase, a self-compartmentalizing cysteine protease. , 1999, Structure.

[9]  J. Neefjes,et al.  The proteasome‐specific inhibitor lactacystin blocks presentation of cytotoxic T lymphocyte epitopes in human and murine cells , 1997, European journal of immunology.

[10]  J. Shabanowitz,et al.  Proteasomes can either generate or destroy MHC class I epitopes: evidence for nonproteasomal epitope generation in the cytosol. , 1998, Journal of immunology.

[11]  Hans-Georg Rammensee,et al.  The Human 26 S and 20 S Proteasomes Generate Overlapping but Different Sets of Peptide Fragments from a Model Protein Substrate* , 2000, The Journal of Biological Chemistry.

[12]  L. Hersh.  Solubilization and characterization of two rat brain membrane-bound aminopeptidases active on Met-enkephalin. , 1981, Biochemistry.

[13]  G. Chelvanayagam,et al.  Proteolytic processing of peptides in the lumen of the endoplasmic reticulum for antigen presentation by major histocompatibility class I , 2000, European journal of immunology.

[14]  T. Elliott,et al.  Processing of major histocompatibility class I-restricted antigens in the endoplasmic reticulum , 1995, The Journal of experimental medicine.

[15]  J. Yewdell,et al.  Trimming of antigenic peptides in an early secretory compartment , 1994, The Journal of experimental medicine.

[16]  L. Hersh,et al.  Studies on the Tissue Distribution of the Puromycin‐Sensitive Enkephalin‐Degrading Aminopeptidases , 1988, Journal of neurochemistry.

[17]  L. Hersh,et al.  Puromycin-sensitive Aminopeptidase , 1995, The Journal of Biological Chemistry.

[18]  K. Carvalho,et al.  An enkephalin degrading aminopeptidase of human brain preserved during the vertebrate phylogeny. , 1991, Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology.

[19]  K. Rajewsky,et al.  MHC class I expression in mice lacking the proteasome subunit LMP-7. , 1994, Science.

[20]  T. Takeuchi,et al.  A bleomycin-inactivating enzyme in mouse liver. , 1974, The Journal of antibiotics.

[21]  M. D. Val,et al.  Selective involvement of proteasomes and cysteine proteases in MHC class I antigen presentation. , 1997, Journal of immunology.

[22]  A. Goldberg,et al.  Interferon-γ Can Stimulate Post-proteasomal Trimming of the N Terminus of an Antigenic Peptide by Inducing Leucine Aminopeptidase* , 1998, The Journal of Biological Chemistry.

[23]  C. Enenkel,et al.  BLH1 codes for a yeast thiol aminopeptidase, the equivalent of mammalian bleomycin hydrolase. , 1993, The Journal of biological chemistry.

[24]  J. Lazo,et al.  Essential binding and functional domains of human bleomycin hydrolase. , 1998, Biochemistry.

[25]  H. Rammensee,et al.  Generation of the vesicular stomatitis virus nucleoprotein cytotoxic T lymphocyte epitope requires proteasome‐dependent and ‐independent proteolytic activities , 1998, European journal of immunology.

[26]  A. Goldberg,et al.  Two distinct proteolytic processes in the generation of a major histocompatibility complex class I-presented peptide. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[27]  P. Cresswell,et al.  The protease inhibitor, N-acetyl-L-leucyl-L-leucyl-leucyl-L- norleucinal, decreases the pool of major histocompatibility complex class I-binding peptides and inhibits peptide trimming in the endoplasmic reticulum , 1996, The Journal of experimental medicine.

[28]  C. Bergmann,et al.  Sequential Cleavage by Metallopeptidases and Proteasomes Is Involved in Processing HIV-1 ENV Epitope for Endogenous MHC Class I Antigen Presentation1 , 2000, The Journal of Immunology.

[29]  D. Payan,et al.  Human bleomycin hydrolase: molecular cloning, sequencing, functional expression, and enzymatic characterization. , 1996, Biochemistry.

[30]  Hans-Georg Rammensee,et al.  Coordinated Dual Cleavages Induced by the Proteasome Regulator PA28 Lead to Dominant MHC Ligands , 1996, Cell.

[31]  J. Yewdell,et al.  Dissociation of proteasomal degradation of biosynthesized viral proteins from generation of MHC class I-associated antigenic peptides. , 1998, Journal of immunology.

[32]  J. Lazo,et al.  An evolutionarily conserved cysteine protease, human bleomycin hydrolase, binds to the human homologue of ubiquitin-conjugating enzyme 9. , 1998, Molecular pharmacology.