A role for the proteasome regulator PA28α in antigen presentation

Groettrup, Marcus; Soza, Andrea; Eggers, Maren; Kuehn, Lothar; Dick, Tobias P.; Schild, Hansjörg; Rammensee, Hans Georg; Koszinowski, Ulrich H.; Kloetzel, Peter M.

doi:10.1038/381166a0

Cited by 323 publications

(196 citation statements)

References 21 publications

Supporting

Mentioning

187

Contrasting

Order By: Relevance

“…As a second approach to address the role of TPP II in NP 147-155 Ag processing, we overexpressed this enzyme and examined presentation of the two NP epitopes. Overexpressing components of the proteasome complex has been shown to enhance epitope presentation in other systems (53)(54)(55), indicating that changes in Ag processing efficiency can be discerned using this approach if the protease in question has a central role in epitope generation. However, substantial differences in levels of TPP II expression failed to alter epitope presentation.…”

Section: Discussionmentioning

confidence: 99%

Re-evaluating the Generation of a “Proteasome-Independent” MHC Class I-Restricted CD8 T Cell Epitope

Wherry

Golovina

Morrison

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

The proteasome is primarily responsible for the generation of MHC class I-restricted CTL epitopes. However, some epitopes, such as NP147–155 of the influenza nucleoprotein (NP), are presented efficiently in the presence of proteasome inhibitors. The pathways used to generate such apparently “proteasome-independent” epitopes remain poorly defined. We have examined the generation of NP147–155 and a second proteasome-dependent NP epitope, NP50–57, using cells adapted to growth in the presence of proteasome inhibitors and also through protease overexpression. We observed that: 1) Ag processing and presentation proceeds in proteasome-inhibitor adapted cells but may become more dependent, at least in part, on nonproteasomal protease(s), 2) tripeptidyl peptidase II does not substitute for the proteasome in the generation of NP147–155, 3) overexpression of leucine aminopeptidase, thymet oligopeptidase, puromycin-sensitive aminopeptidase, and bleomycin hydrolase, has little impact on the processing and presentation of NP50–57 or NP147–155, and 4) proteasome-inhibitor treatment altered the specificity of substrate cleavage by the proteasome using cell-free digests favoring NP147–155 epitope preservation. Based on these results, we propose a central role for the proteasome in epitope generation even in the presence of proteasome inhibitors, although such inhibitors will likely alter cleavage patterns and may increase the dependence of the processing pathway on postproteasomal enzymes.

show abstract

Section: Discussionmentioning

confidence: 99%

Re-evaluating the Generation of a “Proteasome-Independent” MHC Class I-Restricted CD8 T Cell Epitope

Wherry

Golovina

Morrison

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…It plays a major role in controlling cell proliferation [2,3], cell cycle progression [4,5], cell differentiation [6], and gene transcription [7]. Recent evidence also suggests an indispensable role of the ubiquitin-proteasome pathway in MHC class I antigen processing and presentation [8,9]. The 26S proteasome is an essential component of the highly regulated, ATP-dependent proteolysis, which catalyzes the rapid degradation of many proteins of important biological functions such as ornithine decarboxylase (ODC) [10], cell cycle regulatory proteins (e.g.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of an activated 20S proteasome in Trypanosoma brucei

Wang

1997

FEBS Letters

View full text Add to dashboard Cite

“…Section 1734 solely to indicate this fact. icantly enhanced class I-mediated presentation of two viral epitopes (16). The reason for the augmenting effect seems to be favorable modulation of proteasome cleavage activity (17,18).…”

mentioning

confidence: 99%

26 S Proteasome-mediated Production of an Authentic Major Histocompatibility Class I-restricted Epitope from an Intact Protein Substrate

Ben-Shahar¹,

Komlosh²,

Nadav³

et al. 1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

Peptides displayed on the cell surface by major histocompatibility class I molecules (MHC class I) are generated by proteolytic processing of protein-antigens in the cytoplasm. Initially, antigens are degraded by the 26 S proteasome, most probably following ubiquitination. However, it is unclear whether this proteolysis results in the generation of MHC class I ligands or if further processing is required. To investigate the role of the 26 S proteasome in antigen presentation, we analyzed the processing of an intact antigen by purified 26 S proteasome. A recombinant ornithine decarboxylase was produced harboring the H-2K b -restricted peptide epitope, derived from ovalbumin SIINFEKL (termed ODC-ova). Utilizing recombinant antizyme to target the antigen to the 26 S proteasome, we found that proteolysis of ODCova by the 26 S proteasome resulted in the generation of the K b -ligand. Mass spectrometry analysis indicated that in addition to SIINFEKL, the N-terminally extended ligand, HSIINFEKL, was also generated. Production of SIINFEKL was linear with time and directly proportional to the rate of ODC-ova degradation. The overall yield of SIINFEKL was approximately 5% of the amount of ODC-ova degraded. The addition of PA28, the 20 S, or the 20 S-PA28 complex to the 26 S proteasome did not significantly affect the yield of the antigenic peptide. These findings demonstrate that the 26 S proteasome can efficiently digest an intact physiological substrate and generate an authentic MHC class I-restricted epitope. Cells display foreign and altered intracellular antigens to cytotoxic T lymphocytes (CTL)1 through MHC class I molecules. Antigenic peptides presented through class I molecules are generated in the cytoplasm by proteolytic degradation of endogenously synthesized antigens. Suitable peptides are then translocated through specialized peptide transporters (termed TAP) to the lumen of the endoplasmic reticulum, where they bind and subsequently stabilize newly synthesized MHC class I molecules. Assembled class I molecules then migrate to the cell surface for recognition by T cells (1).There is now substantial evidence implicating the proteasome in antigen processing. When membrane-permeable inhibitors of proteasomes were added to cells, they severely inhibited proteasome activity in vitro, the cellular turnover of short and long lived proteins, and assembly of class I molecules as well as presentation of ovalbumin (OVA) introduced into the cytoplasm (2, 3).Proteasomes are multicatalytic complexes that constitute the major proteolytic activity in the cytosol and nucleus of all eukaryotes. Proteasomes are found in the cytoplasm as 20 and 26 S particles. The 20 S proteasome is a barrel-shaped complex consisting of four stacked rings, each composed of seven related subunits. The outer rings are formed by noncatalytic ␣ subunits, whereas catalytic ␤ subunits occupy the inner two rings. The 20 S proteasome is an ATP-independent protease that in vitro cleaves only peptides. It can also digest several unfolded proteins, but onl...

show abstract

A role for the proteasome regulator PA28α in antigen presentation

Cited by 323 publications

References 21 publications

Re-evaluating the Generation of a “Proteasome-Independent” MHC Class I-Restricted CD8 T Cell Epitope

Re-evaluating the Generation of a “Proteasome-Independent” MHC Class I-Restricted CD8 T Cell Epitope

Identification and characterization of an activated 20S proteasome in Trypanosoma brucei

26 S Proteasome-mediated Production of an Authentic Major Histocompatibility Class I-restricted Epitope from an Intact Protein Substrate

Contact Info

Product

Resources

About