This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Grant, J. R.
Right arrow Articles by Jefferies, W. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Grant, J. R.
Right arrow Articles by Jefferies, W. A.

 Previous Article  |  Next Article 

Clinical and Vaccine Immunology, July 2007, p. 907-917, Vol. 14, No. 7
1071-412X/07/$08.00+0     doi:10.1128/CVI.00058-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Identification of a Novel Immunosubversion Mechanism Mediated by a Virologue of the B-Lymphocyte Receptor TACI{triangledown}

Jason R. Grant,{dagger} Alexander R. Moise,{ddagger} and Wilfred A. Jefferies*

The Michael Smith Laboratories, the Biomedical Research Centre, and Departments of Microbiology and Immunology, Medical Genetics, and Zoology, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC V6T 1Z3, Canada

Received 30 January 2007/ Returned for modification 28 March 2007/ Accepted 17 May 2007

TACI (transmembrane activator and calcium modulator and cyclophilin ligand [CAML] interactor) is a part of a novel network of ligands and receptors involved in B-cell survival and isotype switching. The TACI protein mediates its effects through CAML, an endoplasmic reticulum (ER)-localized protein that controls Ca2+ efflux. The adenovirus E3-6.7K protein prevents inflammatory responses and also confers resistance from a variety of apoptotic stimuli and maintains ER Ca2+ homeostasis; however, the mechanism of action is unknown. Here, we provide evidence that E3-6.7K shares sequence homology with TACI and inhibits apoptosis and ER Ca2+ efflux through an interaction with CAML, a Ca2+-modulating protein. We demonstrate a direct interaction between E3-6.7K and CAML and reveal that the two proteins colocalize in an ER-like compartment. Furthermore, the interaction between the two proteins is localized to the N-terminal domain of CAML and to a 22-amino-acid region near the C terminus of E3-6.7K termed the CAML-binding domain (CBD). Mutational analysis of the CBD showed that an interaction with CAML is required for E3-6.7K to inhibit thapsigargin-induced apoptosis and ER Ca2+ efflux. E3-6.7K appears to be the first virologue of TACI to be identified. It targets CAML in a novel immunosubversive mechanism to alter ER Ca2+ homeostasis, which consequently inhibits inflammation and protects infected cells from apoptosis.

* Corresponding author. Mailing address: The Biomedical Research Centre, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Phone: (604) 822-6961. Fax: (604) 822-6780. E-mail: wilf{at}brc.ubc.ca

{triangledown} Published ahead of print on 30 May 2007.

{dagger} Present address: Department of Agriculture, Food and Nutritional Science, University of Alberta, Edmonton, Alberta T6G 2P5, Canada.

{ddagger} Present address: Department of Ophthalmology, University of Washington, Seattle, WA 98195-6485.

Clinical and Vaccine Immunology, July 2007, p. 907-917, Vol. 14, No. 7
1071-412X/07/$08.00+0     doi:10.1128/CVI.00058-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»