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Journal of Virology, November 2005, p. 13606-13617, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13606-13617.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mechanism for Removal of Tumor Necrosis Factor Receptor 1 from the Cell Surface by the Adenovirus RID{alpha}/ß Complex{ddagger}

Y. Rebecca Chin1* and Marshall S. Horwitz1,2,{dagger}

Department of Microbiology and Immunology, Forchheimer Building, Room 411,1 Division of Infectious Diseases, Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York 104612

Received 9 June 2005/ Accepted 9 August 2005

Proteins encoded in adenovirus early region 3 have important immunoregulatory properties. We have recently shown that the E3-10.4K/14.5K (RID{alpha}/ß) complex downregulates tumor necrosis factor receptor 1 (TNFR1) expression at the plasma membrane. To study the role of the RIDß tyrosine sorting motif in the removal of surface TNFR1, tyrosine 122 on RIDß was mutated to alanine or phenylalanine. Both RIDß mutations not only abolished the downregulation of surface TNFR1 but paradoxically increased surface TNFR1 levels. RID also downregulates other death receptors, such as FAS; however, surface FAS expression was not increased by RIDß mutants, suggesting that regulation of TNFR1 and that of FAS by RID are mechanistically different. In the mixing experiments, the wild-type (WT) RID-mediated TNFR1 downregulation was partially inhibited in the presence of RIDß mutants, indicating that the mutants compete for TNFR1 access. Indeed, an association between RIDß and TNFR1 was shown by coimmunoprecipitation. In contrast, the mutants did not affect the WT RID-induced downregulation of FAS. These differential effects support a model in which RID associates with TNFR1 on the plasma membrane, whereas RID probably associates with FAS in a cytoplasmic compartment. By using small interfering RNA against the µ2 subunit of adaptor protein 2, dominant negative dynamin construct K44A, and the lysosomotropic agents bafilomycin A1 and ammonium chloride, we also demonstrated that surface TNFR1 was internalized by RID by a clathrin-dependent process involving µ2 and dynamin, followed by degradation of TNFR1 via an endosomal/lysosomal pathway.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Forchheimer Building, Room 411, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-3625. Fax: (718) 430-8702. E-mail: ychin{at}aecom.yu.edu.

{ddagger} Dedicated to the memory of Marshall Horwitz.

{dagger} Deceased.

Journal of Virology, November 2005, p. 13606-13617, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13606-13617.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • 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]  
  • Cianciola, N. L., Crooks, D., Shah, A. H., Carlin, C. (2007). A Tyrosine-Based Signal Plays a Critical Role in the Targeting and Function of Adenovirus RID{alpha} Protein. J. Virol. 81: 10437-10450 [Abstract] [Full Text]  
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