Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Immunol ; 208(12): 2817-2828, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35688464

RESUMO

By tying peptide fragments originally distant in parental proteins, the proteasome can generate spliced peptides that are recognized by CTL. This occurs by transpeptidation involving a peptide-acyl-enzyme intermediate and another peptide fragment present in the catalytic chamber. Four main subtypes of proteasomes exist: the standard proteasome (SP), the immunoproteasome, and intermediate proteasomes ß1-ß2-ß5i (single intermediate proteasome) and ß1i-ß2-ß5i (double intermediate proteasome). In this study, we use a tandem mass tag-quantification approach to study the production of six spliced human antigenic peptides by the four proteasome subtypes. Peptides fibroblast growth factor-5172-176/217-220, tyrosinase368-373/336-340, and gp10040-42/47-52 are better produced by the SP than the other proteasome subtypes. The peptides SP110296-301/286-289, gp100195-202/191or192, and gp10047-52/40-42 are better produced by the immunoproteasome and double intermediate proteasome. The current model of proteasome-catalyzed peptide splicing suggests that the production of a spliced peptide depends on the abundance of the peptide splicing partners. Surprisingly, we found that despite the fact that reciprocal peptides RTK_QLYPEW (gp10040-42/47-52) and QLYPEW_RTK (gp10047-52/40-42) are composed of identical splicing partners, their production varies differently according to the proteasome subtype. These differences were maintained after in vitro digestions involving identical amounts of the splicing fragments. Our results indicate that the amount of splicing partner is not the only factor driving peptide splicing and suggest that peptide splicing efficiency also relies on other factors, such as the affinity of the C-terminal splice reactant for the primed binding site of the catalytic subunit.


Assuntos
Peptídeos , Complexo de Endopeptidases do Proteassoma , Antígenos/metabolismo , Humanos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Peptídeos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Splicing de RNA
2.
Mol Immunol ; 113: 93-102, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-29650230

RESUMO

CD8+ cytolytic T lymphocytes are essential players of anti-tumor immune responses. On tumors, they recognize peptides of about 8-to-10 amino acids that generally result from the degradation of cellular proteins by the proteasome. Until a decade ago, these peptides were thought to solely correspond to linear fragments of proteins that were liberated after the hydrolysis of the peptide bonds located at their extremities. However, several examples of peptides containing two fragments originally distant in the protein sequence challenged this concept and demonstrated that proteasome could also splice peptides together by creating a new peptide bond between two distant fragments. Unexpectedly, peptide splicing emerges as an essential way to increase the peptide repertoire diversity as these spliced peptides were shown to represent up to 25% of the peptides presented on a cell by MHC class I. Here, we review the different steps that led to the discovery of peptide splicing by the proteasome as well as the lightening offered by the recent progresses of mass spectrometry and bioinformatics in the analysis of the spliced peptide repertoire.


Assuntos
Peptídeos/genética , Complexo de Endopeptidases do Proteassoma/genética , Splicing de RNA/genética , Animais , Linfócitos T CD8-Positivos/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Peptídeos/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Splicing de RNA/imunologia
3.
J Immunol ; 201(7): 1875-1888, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30135181

RESUMO

Cancer immunotherapy has been flourishing in recent years with remarkable clinical success. But as more patients are treated, a shadow is emerging that has haunted other cancer therapies: tumors develop resistance. Resistance is often caused by defects in the MHC class I Ag presentation pathway critical for CD8 T cell-mediated tumor clearance. TAP and tapasin, both key players in the pathway, are frequently downregulated in human cancers, correlating with poor patient survival. Reduced dependence on these factors may promote vaccine efficiency by limiting immune evasion. In this study, we demonstrate that PMEL209-217, a promising phase 3 trial-tested antimelanoma vaccine candidate, is robustly presented by various TAP- and/or tapasin-deficient cell lines. This striking characteristic may underlie its potency as a vaccine. Surprisingly, cytosolic proteasomes generate the peptide even for TAP-independent presentation, whereas tripeptidyl peptidase 2 (TPP2) efficiently degrades the epitope. Consequently, inhibiting TPP2 substantially boosts PMEL209-217 presentation, suggesting a possible strategy to improve the therapeutic efficacy of the vaccine.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunoterapia Adotiva/métodos , Melanoma/imunologia , Vacinas/imunologia , Aminopeptidases/metabolismo , Apresentação de Antígeno , Linfócitos T CD8-Positivos/transplante , Linhagem Celular Tumoral , Citosol/metabolismo , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Antígeno HLA-A2/metabolismo , Humanos , Evasão da Resposta Imune , Proteínas de Membrana Transportadoras/genética , Oligopeptídeos/genética , Serina Endopeptidases/metabolismo , Antígeno gp100 de Melanoma/imunologia , Antígeno gp100 de Melanoma/metabolismo
4.
J Biol Chem ; 292(51): 21170-21179, 2017 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-29109146

RESUMO

The proteasome is the major protease responsible for the production of antigenic peptides recognized by CD8+ cytolytic T cells (CTL). These peptides, generally 8-10 amino acids long, are presented at the cell surface by major histocompatibility complex (MHC) class I molecules. Originally, these peptides were believed to be solely derived from linear fragments of proteins, but this concept was challenged several years ago by the isolation of anti-tumor CTL that recognized spliced peptides, i.e. peptides composed of fragments distant in the parental protein. The splicing process was shown to occur in the proteasome through a transpeptidation reaction involving an acyl-enzyme intermediate. Here, we review the steps that led to the discovery of spliced peptides as well as the recent advances that uncover the unexpected importance of spliced peptides in the composition of the MHC class I repertoire.


Assuntos
Linfócitos T CD8-Positivos/enzimologia , Modelos Biológicos , Modelos Moleculares , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína , Animais , Biocatálise , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Membrana Celular/metabolismo , Biologia Computacional , Humanos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Peptidil Transferases/química , Peptidil Transferases/metabolismo , Complexo de Endopeptidases do Proteassoma/química , Conformação Proteica , Multimerização Proteica , Proteômica/métodos , Proteômica/tendências , Propriedades de Superfície
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...