Two distinct proteolytic processes in the generation of a major histocompatibility complex class I-presented peptide

Craiu, Abie; Akopian, Tatos; Goldberg, Alfred L.; Rock, Kenneth L.

doi:10.1073/pnas.94.20.10850

Cited by 253 publications

(256 citation statements)

References 42 publications

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“…In the cytosol, proteasomes generate most correct carboxyl termini of epitopes (39). In contrast, peptidases producing the carboxyl terminus in the secretory pathway have only been indirectly implicated by our results, where a minimal size CMV 9pp89 peptide was naturally produced from a construct similar to sC-Ova (8).…”

Section: Discussionmentioning

confidence: 52%

Furin-Processed Antigens Targeted to the Secretory Route Elicit Functional TAP1−/−CD8+ T Lymphocytes In Vivo

Medina

Ramos²,

Iborra³

et al. 2009

The Journal of Immunology

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Most pathogen-derived peptides recognized by CD8+ CTL are produced by proteasomes and delivered to the endoplasmic reticulum by the TAP transporters associated with Ag processing. Alternative proteases also produce antigenic peptides, but their actual relevance is unclear. There is a need to quantify the contribution of these supplementary pathways in vitro and in vivo. A well-defined TAP-independent secretory route of Ag processing involves the trans-Golgi network protease furin. Quantitation of this route by using OVA constructs encoded by vaccinia viruses indicates that it provides approximately one-third of all surface complexes of peptide and MHC class I molecules. Generation of the epitope carboxyl terminus is a dramatic rate-limiting step, since bypassing it increased efficiency by at least 1000-fold. Notably, the secretory construct activated a similar percentage of Ag-specific CD8+ T cells in wild type as in TAP1-deficient mice, which allow only secretory routes but which have a 10- to 20-fold smaller CD8 compartment. Moreover, these TAP1−/− OVA-specific CD8+ T lymphocytes accomplished elimination of epitope-bearing cells in vivo. The results obtained with this experimental system underscore the potential of secretory pathways of MHC class I Ag presentation to elicit functional CD8+ T lymphocytes in vivo and support the hypothesis that noncytosolic processing mechanisms may compensate in vivo for the lack of proteasome participation in Ag processing in persons genetically deficient in TAP and thus contribute to pathogen control.

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Section: Discussionmentioning

confidence: 52%

Furin-Processed Antigens Targeted to the Secretory Route Elicit Functional TAP1−/−CD8+ T Lymphocytes In Vivo

Medina

Ramos²,

Iborra³

et al. 2009

The Journal of Immunology

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“…A prerequisite for the induction of a CTL response is the generation of peptides from their precursor polypeptides. The major cytosolic protease associated with the generation of antigenic peptides -in particular the C-terminal end of the peptides -is the proteasome [2][3][4][5][6]. After protea-somal cleavage the peptides may be trimmed at the Nterminal end by other peptidases in the cytosol [7].…”

Section: Introductionmentioning

confidence: 99%

An integrative approach to CTL epitope prediction: A combined algorithm integrating MHC class I binding, TAP transport efficiency, and proteasomal cleavage predictions

Larsen

Lundegaard

Lamberth³

et al. 2005

Eur. J. Immunol.

285

254

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Reverse immunogenetic approaches attempt to optimize the selection of candidate epitopes, and thus minimize the experimental effort needed to identify new epitopes. When predicting cytotoxic T cell epitopes, the main focus has been on the highly specific MHC class I binding event. Methods have also been developed for predicting the antigen-processing steps preceding MHC class I binding, including proteasomal cleavage and transporter associated with antigen processing (TAP) transport efficiency. Here, we use a dataset obtained from the SYFPEITHI database to show that a method integrating predictions of MHC class I binding affinity, TAP transport efficiency, and Cterminal proteasomal cleavage outperforms any of the individual methods. Using an independent evaluation dataset of HIV epitopes from the Los Alamos database, the validity of the integrated method is confirmed. The performance of the integrated method is found to be significantly higher than that of the two publicly available prediction methods BIMAS and SYFPEITHI. To identify 85% of the epitopes in the HIV dataset, 9% and 10% of all possible nonamers in the HIV proteins must be tested when using the BIMAS and SYFPEITHI methods, respectively, for the selection of candidate epitopes. This number is reduced to 7% when using the integrated method. In practical terms, this means that the experimental effort needed to identify an epitope in a hypothetical protein with 85% probability is reduced by 20-30% when using the integrated method. The method is available at

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“…Further, even in studies of cell lines, ER processing of peptide fragments is not invariably observed. Although N-terminal trimming can occur, the ability to process the C-terminal end of peptides is still controversial (13,24).…”

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confidence: 99%

“…Further, animals with a deletion of proteasome subunits or the proteasome regulator, PA28 show a decrease in class I expression and/or the generation of specific class I epitopes (8 -10). In addition to the proteasome, other proteases have also been implicated in the processing of protein precursors (11)(12)(13)(14)(15)(16). The relative contribution of different proteases to class I Ag processing has not been established.…”

mentioning

confidence: 99%

Factors Controlling the Trafficking and Processing of a Leader-Derived Peptide Presented by Qa-1

Bai

Aldrich

Forman

2000

The Journal of Immunology

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Many leader-derived peptides require TAP for presentation by class I molecules. This TAP dependence can either be ascribed to the inability of proteases resident in the endoplasmic reticulum (ER) to trim leader peptide precursors into the appropriate epitope or the failure of a portion of the leader segment to gain access to the lumen of the ER. Using the Qa-1 binding epitope, Qdm derived from a class Ia leader as a model, we show that many cell types lack ER protease activity to trim this peptide at its C terminus. However, both T1 and T2 cells contain appropriate protease activity to process the full length Dd leader (DL) when introduced into the ER lumen. Nevertheless, both T1 cells treated with the TAP inhibitor ICP47 and TAP− T2 cells fail to present this epitope from either the intact Dd molecule or a minigene encoding the DL. This indicates that the portion of the leader containing Qdm does not gain access to the ER. However, changing the Arg at P7 of the DL to a Cys can alter its trafficking and allows for TAP-independent presentation of the Qdm epitope.

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Two distinct proteolytic processes in the generation of a major histocompatibility complex class I-presented peptide

Cited by 253 publications

References 42 publications

Furin-Processed Antigens Targeted to the Secretory Route Elicit Functional TAP1−/−CD8+ T Lymphocytes In Vivo

Furin-Processed Antigens Targeted to the Secretory Route Elicit Functional TAP1−/−CD8+ T Lymphocytes In Vivo

An integrative approach to CTL epitope prediction: A combined algorithm integrating MHC class I binding, TAP transport efficiency, and proteasomal cleavage predictions

Factors Controlling the Trafficking and Processing of a Leader-Derived Peptide Presented by Qa-1

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