Three adenovirus E3 proteins cooperate to evade apoptosis by tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and -2.
Adenovirus encodes multiple gene products that regulate proapoptotic cellular responses to viral infection mediated by both the innate and adaptive immune systems. The E3-10.4K and 14.5K gene products are known to modulate the death receptor Fas. In this study, we demonstrate that an additional viral E3 protein, 6.7K, functions in the specific modulation of the two death receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The 6.7K protein is expressed on the cell surface and forms a complex with the 10.4K and 14.5K proteins, and this complex is sufficient to induce down-modulation of TRAIL receptor-1 and -2 from the cell surface and reverse the sensitivity of infected cells to TRAIL-mediated apoptosis. Down-modulation of TRAIL-R2 by the E3 complex is dependent on the cytoplasmic tail of the receptor, but the death domain alone is not sufficient. These results identify a mechanism for viral modulation of TRAIL receptor-mediated apoptosis and suggest the E3 protein complex has evolved to regulate the signaling of selected cytokine receptors.
Benedict
C A
CA
Division of Molecular Immunology and the Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
Norris
P S
PS
Prigozy
T I
TI
Bodmer
J L
JL
Mahr
J A
JA
Garnett
C T
CT
Martinon
F
F
Tschopp
J
J
Gooding
L R
LR
Ware
C F
CF
D000256:Adenoviridae / Q000378:metabolism; D017503:Adenovirus E3 Proteins / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis; D015536:Down-Regulation; D053222:Fas Ligand Protein; D019073:HT29 Cells / Q000821:virology; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins; D018121:Receptors, Cytokine / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions; D019014:fas Receptor / Q000378:metabolism
D017503:Adenovirus E3 Proteins; C087149:E3-6.7K protein, Adenovirus; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018121:Receptors, Cytokine; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; D019014:fas Receptor