Identification of a Novel Immunosubversion Mechanism Mediated by a Virologue of the B-Lymphocyte Receptor TACI
Grant, Jason R.
Moise, Alexander R.
Jefferies, Wilfred A.
The American Society fro Microbiology
Scholarly/refereed, publisher version
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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.
Grant, Jason R., Alexander R. Moise, and Wilfred A. Jefferies. "Identification of a Novel Immunosubversion Mechanism Mediated by a Virologue of the B-Lymphocyte Receptor TACI." Clin Vaccine Immunol July 2007 vol. 14 no. 7 907-917. http://dx.doi.org/10.1128/CVI.00058-07
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