Identification of a novel immunosubversion mechanism mediated by a virologue of the B-lymphocyte receptor TACI.
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 Ca(2+) efflux. The adenovirus E3-6.7K protein prevents inflammatory responses and also confers resistance from a variety of apoptotic stimuli and maintains ER Ca(2+) 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 Ca(2+) efflux through an interaction with CAML, a Ca(2+)-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 Ca(2+) 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 Ca(2+) homeostasis, which consequently inhibits inflammation and protects infected cells from apoptosis.
Grant
Jason R
JR
The Michael Smith Laboratories, The Biomedical Research Centre, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada. wilf@brc.ubc.ca
Moise
Alexander R
AR
Jefferies
Wilfred A
WA
D000256:Adenoviridae / Q000235:genetics; D017503:Adenovirus E3 Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006367:HeLa Cells; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding / Q000276:immunology; D014162:Transfection; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D017503:Adenovirus E3 Proteins; C087149:E3-6.7K protein, Adenovirus; D008024:Ligands; D008565:Membrane Proteins; C108467:TNFRSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D002118:Calcium