HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 52, 39925-39934, December 29, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/52/39925    most recent M608522200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Guil, S. Articles by Del Val, M. Search for Related Content PubMed PubMed Citation Articles by Guil, S. Articles by Del Val, M. Social Bookmarking                      What's this?

Need for Tripeptidyl-peptidase II in Major Histocompatibility Complex Class I Viral Antigen Processing when Proteasomes are Detrimental^*

Sara Guil¹, Marta Rodríguez-Castro¹², Francisco Aguilar²⁵, Eugenia M. Villasevil²³, Luis C. Antón, and Margarita Del Val⁴

From the Unidad de Inmunología Viral, Centro Nacional de Microbiología, Instituto de Salud Carlos III, E-28220 Majadahonda (Madrid), Spain and Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid, E-28049 Madrid, Spain

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.

Received for publication, September 5, 2006 , and in revised form, October 24, 2006.

^* This work was supported in part by grants from Spanish Ministerio de Educación y Ciencia and from Instituto de Salud Carlos III (to M. D. V.), by a grant from Spanish Ministerio de Educación y Ciencia (to L. C. A.), by an institutional grant from the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa, and by a grant from Comunidad de Madrid (to M. D. V. and L. C. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Instituto de Salud Carlos III.

² These authors contributed equally to this work.

⁵ Supported by Instituto de Salud Carlos III through Red Temática de Investigación Cooperativa en SIDA (RIS).

³ Supported by a FPI fellowship from Spanish Ministerio de Educación y Ciencia.

⁴ To whom correspondence should be addressed: Unidad de Inmunología Viral, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Ctra. Pozuelo km 2, E-28220 Majadahonda (Madrid), Spain. Tel.: 34-918-223-926; Fax: 34-915-097-919; E-mail: mdval{at}isciii.es.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Johnstone, S. Guil, M. A. Rico, B. Garcia-Barreno, D. Lopez, J. A. Melero, and M. Del Val Relevance of viral context and diversity of antigen-processing routes for respiratory syncytial virus cytotoxic T-lymphocyte epitopes J. Gen. Virol., September 1, 2008; 89(9): 2194 - 2203. [Abstract] [Full Text] [PDF]

				C.J. Carter Schizophrenia Susceptibility Genes Directly Implicated in the Life Cycles of Pathogens: Cytomegalovirus, Influenza, Herpes simplex, Rubella, and Toxoplasma gondii Schizophr Bull, June 13, 2008; (2008) sbn054v1. [Abstract] [Full Text] [PDF]

				E. Firat, J. Huai, L. Saveanu, S. Gaedicke, P. Aichele, K. Eichmann, P. van Endert, and G. Niedermann Analysis of Direct and Cross-Presentation of Antigens in TPPII Knockout Mice1 J. Immunol., December 15, 2007; 179(12): 8137 - 8145. [Abstract] [Full Text] [PDF]

				M. Marcilla, J. J. Cragnolini, and J. A. Lopez de Castro Proteasome-independent HLA-B27 Ligands Arise Mainly from Small Basic Proteins Mol. Cell. Proteomics, May 1, 2007; 6(5): 923 - 938. [Abstract] [Full Text] [PDF]