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

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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.

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