This Article Full Text (PDF) Other Versions of this Article: CVI.00058-07v1 14/7/907    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Grant, J. R. Articles by Jefferies, W. A. Search for Related Content PubMed PubMed Citation Articles by Grant, J. R. Articles by Jefferies, W. A.

 Previous Article  |  Next Article 

Clin. Vaccine Immunol. doi:10.1128/CVI.00058-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Identification of a novel immunosubversion mechanism mediated by a virologue of B lymphocyte TACI

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

^* To whom correspondence should be addressed. Email: wilf{at}unixg.ubc.ca.

	Abstract

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 endoplasmic reticulum 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 co-localize 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.