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Journal of Virology, November 2003, p. 11685-11696, Vol. 77, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.21.11685-11696.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Distinct Domains in the Adenovirus E3 RID{alpha} Protein Are Required for Degradation of Fas and the Epidermal Growth Factor Receptor

Tom A. Zanardi,1,{dagger} Soonpin Yei,1,{ddagger} Drew L. Lichtenstein,2 Ann E. Tollefson,1 and William S. M. Wold1,2*

Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, St. Louis, Missouri 63104,1 VirRx Incorporated, St. Louis, Missouri 630172

Received 5 June 2003/ Accepted 8 August 2003

Adenovirus (Ad) types 2 and 5 encode at least five proteins within the E3 transcription unit that help the virus evade the immune system. Two such proteins, RID{alpha} (formerly E3-10.4K) and RIDß (formerly E3-14.5K), form the RID (receptor internalization and degradation) complex (formerly E3-10.4K/14.5K). RID mediates clearance from the cell surface and lysosomal degradation of a number of important members in the tumor necrosis factor receptor (TNFR) superfamily and the receptor tyrosine kinase receptor family. Affected receptors include Fas, TRAIL (TNF-related apoptosis-inducing ligand) receptor 1 (TR1), TR2, and epidermal growth factor receptor (EGFR). Degradation of Fas and TRAIL receptors protects Ad-infected cells from apoptosis. To investigate the mechanism of action of RID{alpha}, 14 mutant RID{alpha} proteins, each containing a three- to five-amino-acid deletion, were constructed and then expressed from the E3 region of a replication-competent recombinant Ad in the same context as wild-type RID{alpha}. Each mutant protein was characterized with regard to five physical properties associated with wild-type RID{alpha}, namely, protein stability, proteolytic cleavage, insertion into the membrane, complex formation with RIDß, and transport to the cell surface. Additionally, the mutant proteins were tested for their ability to mediate internalization and degradation of EGFR and Fas and to protect cells from Fas-mediated apoptosis. The majority of mutant RID{alpha} proteins (8 out of 14) were physically similar to wild-type RID{alpha}. With regard to functional characteristics, the cytoplasmic domain of RID{alpha} is largely unimportant for receptor internalization and degradation and the extracellular domain of RID{alpha} is important for down-regulation of EGFR but not Fas.

* Corrresponding author. Mailing address: Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, 1402 South Grand Blvd., St. Louis, MO 63104. Phone: (314) 577-8435. Fax: (314) 773-3403. E-mail: woldws{at}slu.edu.

{dagger} Present address: Department of Toxicology, Sierra Biomedical, Sparks, NV 89431.

{ddagger} Present address: MedCell Biologics, San Diego, CA 92131.

Journal of Virology, November 2003, p. 11685-11696, Vol. 77, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.21.11685-11696.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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