title: Need for tripeptidyl-peptidase II in major histocompatibility complex class I viral antigen processing when proteasomes are detrimental.
abstract: CD8(+) T lymphocytes recognize infected cells that display virus-derived antigenic peptides complexed with major histocompatibility complex class I molecules. Peptides are mainly byproducts of cellular protein turnover by cytosolic proteasomes. Cytosolic tripeptidyl-peptidase II (TPPII) also participates in protein degradation. Several peptidic epitopes unexpectedly do not require proteasomes, but it is unclear which proteases generate them. We studied antigen processing of influenza virus nucleoprotein epitope NP(147-155), an archetype epitope that is even destroyed by a proteasome-mediated mechanism. TPPII, with the assistance of endoplasmic reticulum trimming metallo-aminopeptidases, probably ERAAP (endoplasmic reticulum aminopeptidase associated with antigen processing), was crucial for nucleoprotein epitope generation both in the presence of functional proteasomes and when blocked by lactacystin, as shown with specific chemical inhibitors and gene silencing. Different protein contexts and subcellular targeting all allowed epitope processing by TPPII as well as trimming. The results show the plasticity of the cell's assortment of proteases for providing ligands for recognition by antiviral CD8(+) T cells. Our observations identify for the first time a set of proteases competent for antigen processing of an epitope that is susceptible to destruction by proteasomes.
authors.affiliation: Unidad de Inmunología Viral, Centro Nacional de Microbiología, Instituto de Salud Carlos III, E-28220 Majadahonda (Madrid), Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Guil
authors.forename: Marta
authors.initials: M
authors.lastname: Rodríguez-Castro
authors.forename: Francisco
authors.initials: F
authors.lastname: Aguilar
authors.forename: Eugenia M
authors.initials: EM
authors.lastname: Villasevil
authors.forename: Luis C
authors.initials: LC
authors.lastname: Antón
authors.forename: Margarita
authors.initials: M
authors.lastname: Del Val
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000595:Amino Acid Sequence; D000626:Aminopeptidases; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006868:Hydrolysis; D009980:Influenza A virus / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D007739:L Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D061988:Proteasome Inhibitors; D016601:RNA-Binding Proteins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D012697:Serine Endopeptidases / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014616:Vaccinia virus / Q000201:enzymology / Q000276:immunology; D014758:Viral Core Proteins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D061988:Proteasome Inhibitors; D016601:RNA-Binding Proteins; D015842:Serine Proteinase Inhibitors; D014758:Viral Core Proteins; C067713:lactacystin; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine