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Journal of Virology, October 2007, p. 10437-10450, Vol. 81, No. 19
0022-538X/07/$08.00+0     doi:10.1128/JVI.00399-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Tyrosine-Based Signal Plays a Critical Role in the Targeting and Function of Adenovirus RID Protein

Nicholas L. Cianciola,¹ Denise Crooks,^1,2, Ankur H. Shah,^1,2 and Cathleen Carlin^1,2,3*

Department of Physiology and Biophysics,¹ Molecular Virology Training Program,² Case Western Reserve University Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4970³

Received 23 February 2007/ Accepted 9 July 2007

Early region 3 genes of human adenoviruses contribute to the virus life cycle by altering the trafficking of cellular proteins involved in adaptive immunity and inflammatory responses. The ability of early region 3 genes to target specific molecules suggests that they could be used to curtail pathological processes associated with these molecules and treat human disease. However, this approach requires genetic dissection of the multiple functions attributed to early region 3 genes. The purpose of this study was to determine the role of targeting on the ability of the early region 3-encoded protein RID to downregulate the EGF receptor. A fusion protein between the RID cytoplasmic tail and glutathione S-transferase was used to isolate clathrin-associated adaptor 1 and adaptor 2 protein complexes from mammalian cells. Deletion and site-directed mutagenesis studies showed that residues 71-AYLRH of RID are necessary for in vitro binding to both adaptor complexes and that Tyr72 has an important role in these interactions. In addition, RID containing a Y72A point mutation accumulates in the trans-Golgi network and fails to downregulate the EGF receptor when it is introduced into mammalian cells as a transgene. Altogether, our data suggest a model where RID is trafficked directly from the trans-Golgi network to an endosomal compartment, where it intercepts EGF receptors undergoing constitutive recycling to the plasma membrane and redirects them to lysosomes.

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* Corresponding author. Mailing address: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-4970. Phone: (216) 368-8939. Fax: (216) 368-3952. E-mail: cathleen.carlin{at}case.edu

Published ahead of print on 18 July 2007.

Present address: Technology Transfer Branch, National Cancer Institute, Executive Plaza South, Suite 450, 6120 Executive Boulevard, Bethesda, MD 20892.

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Journal of Virology, October 2007, p. 10437-10450, Vol. 81, No. 19
0022-538X/07/$08.00+0     doi:10.1128/JVI.00399-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Cianciola, N. L., Carlin, C. R. (2009). Adenovirus RID-{alpha} activates an autonomous cholesterol regulatory mechanism that rescues defects linked to Niemann-Pick disease type C. JCB 187: 537-552 [Abstract] [Full Text]  
• Shah, A. H., Cianciola, N. L., Mills, J. L., Sonnichsen, F. D., Carlin, C. (2007). Adenovirus RID{alpha} regulates endosome maturation by mimicking GTP-Rab7. JCB 179: 965-980 [Abstract] [Full Text]