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

J. Biol. Chem., Vol. 283, Issue 19, 13428-13436, May 9, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/19/13428    most recent M800226200v1 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 Loch, S. Articles by Tampé, R. Search for Related Content PubMed PubMed Citation Articles by Loch, S. Articles by Tampé, R. Social Bookmarking                      What's this?

Signaling of a Varicelloviral Factor across the Endoplasmic Reticulum Membrane Induces Destruction of the Peptide-loading Complex and Immune Evasion^*

Sandra Loch, Florian Klauschies, Christian Schölz, Marieke C. Verweij, Emmanuel J. H. J. Wiertz, Joachim Koch¹, and Robert Tampé²

From the Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, D-60438, Frankfurt/Main, Germany and the Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Cytotoxic T lymphocytes eliminate infected cells upon surface display of antigenic peptides on major histocompatibility complex I molecules. To promote immune evasion, UL49.5 of several varicelloviruses interferes with the pathway of major histocompatibility complex I antigen processing. However, the inhibition mechanism has not been elucidated yet. Within the macromolecular peptide-loading complex we identified the transporter associated with antigen processing (TAP1 and TAP2) as the prime target of UL49.5. Moreover, we determined the active oligomeric state and crucial elements of the viral factor. Remarkably, the last two residues of the cytosolic tail of UL49.5 are essential for endoplasmic reticulum (ER)-associated proteasomal degradation of TAP. However, this process strictly requires additional signaling of an upstream regulatory element in the ER lumenal domain of UL49.5. Within this new immune evasion mechanism, we show for the first time that additive elements of a small viral factor and their signaling across the ER membrane are essential for targeted degradation of a multi-subunit membrane complex.

Received for publication, January 9, 2008 , and in revised form, February 14, 2008.

^* This work was supported by the Deutsche Forschungsgemeinschaft. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

¹ To whom correspondence may be addressed. Tel.: 49-69-798-29475; Fax: 49-69-798-29495; E-mail: joachim.koch{at}em.uni-frankfurt.de.

² To whom correspondence may be addressed. Tel.: 49-69-798-29475; Fax: 49-69-798-29495; E-mail: tampe{at}em.uni-frankfurt.de.

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

This article has been cited by other articles:

				D. Horst, D. van Leeuwen, N. P. Croft, M. A. Garstka, A. D. Hislop, E. Kremmer, A. B. Rickinson, E. J. H. J. Wiertz, and M. E. Ressing Specific Targeting of the EBV Lytic Phase Protein BNLF2a to the Transporter Associated with Antigen Processing Results in Impairment of HLA Class I-Restricted Antigen Presentation J. Immunol., February 15, 2009; 182(4): 2313 - 2324. [Abstract] [Full Text] [PDF]

				M. C. Verweij, D. Koppers-Lalic, S. Loch, F. Klauschies, H. de la Salle, E. Quinten, P. J. Lehner, A. Mulder, M. R. Knittler, R. Tampe, et al. The Varicellovirus UL49.5 Protein Blocks the Transporter Associated with Antigen Processing (TAP) by Inhibiting Essential Conformational Transitions in the 6+6 Transmembrane TAP Core Complex J. Immunol., October 1, 2008; 181(7): 4894 - 4907. [Abstract] [Full Text] [PDF]