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J. Biol. Chem., Vol. 278, Issue 51, 51872-51884, December 19, 2003

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Two Distinct Transport Motifs in the Adenovirus E3/10.4-14.5 Proteins Act in Concert to Down-modulate Apoptosis Receptors and the Epidermal Growth Factor Receptor^*

Annette Hilgendorf, Johan Lindberg, Zsolt Ruzsics, Stefan Höning¶, Andreas Elsing||, Madelaine Löfqvist**, Hartmut Engelmann, and Hans-Gerhard Burgert¶¶

From the Gene Centre of the Ludwig-Maximilians-University, Department of Virology, 81377 München, Germany, the ^¶Institute for Biochemistry II, Georg-August University, 37073 Göttingen, Germany, the Institute for Immunology, University München, 80336 München, Germany, and the Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom

The adenovirus (Ad) early transcription unit E3 encodes immunosubversive functions. The E3 transmembrane proteins 10.4 and 14.5 form a complex that down-regulates the epidermal growth factor receptor and apoptosis receptors from the cell surface by diverting them to endosomes/lysosomes for degradation. The latter process protects infected cells from ligand-induced apoptosis. The mechanism by which 10.4-14.5 mediate re-routing remains elusive. We examined the role of putative YXX and dileucine (LL) transport motifs within Ad2 10.4-14.5 for target protein modulation. By generating stable E3 transfectants expressing 10.4-14.5 proteins with alanine substitutions in these motifs, we show that 3 of the 5 motifs are essential for functional activity. Whereas tyrosine 74 in 14.5 appears to be important for efficient 10.4-14.5 interaction, the ¹²²YXX motif in 14.5 and the dileucine motif Leu ⁸⁷-Leu⁸⁸ in 10.4 constitute genuine transport motifs: disruption of either motif abolished binding to the cellular adaptor proteins AP-1 and AP-2, as shown by surface plasmon resonance spectroscopy, and caused missorting, dramatically altering cell surface appearance and the intracellular location of viral proteins. Fluorescence-activated cell sorter analysis and immunofluorescence data provide evidence that Tyr¹²² in 14.5 is essential for rapid endocytosis of the 10.4-14.5 complex, whereas the 10.4LL motif acts down-stream and protects 10.4-14.5 from extensive degradation by rerouting it into a recycling pathway. Infection of primary cells with adenoviruses carrying the relevant point mutations confirmed the crucial role of these transport motifs for down-regulation of Fas, TRAIL-R1, TRAIL-R2, and epidermal growth factor receptor. Thus, two distinct transport motifs present in two proteins synergize for efficient target removal and immune evasion.

Received for publication, September 10, 2003

^* This work was supported in part by Grants Bu 642/4-2 and SFB 455 (to H.-G. B.) from the Deutsche Forschungsgemeinschaft (DFG). 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.

Present address: Amersham-Pharmacia Biotech, Stockholm, Sweden.

^|| MacoPharma GmbH, 63225 Langen, Germany.

^** Present address: Gesellschaft für Strahlen- und Umweltforschung, Hämatologikum, 81377 München, Germany.

^¶¶ To whom correspondence should be addressed: Dept. of Biological Sciences, University of Warwick, Coventry, CV4 7AL, United Kingdom. Tel.: 44-2476-524-744; Fax: 44-2476-523-568; E-mail: H-G.Burgert{at}warwick.ac.uk.

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