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 cellul ar responses to viral infection mediated by both the innate and adaptive im mune systems. The E3-10.4K and 14.5K gene products are known to modulate th e death receptor Fas. In this study, we demonstrate that an additional vira l E3 protein, 6.7K, functions in the specific modulation of the two death r eceptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL ), The 6.7K protein is expressed on the cell surface and forms a complex wi th the 10.4K and 14.5K proteins, and this complex is sufficient to induce d own-modulation of TRAIL receptor-1 and -2 from the cell surface and reverse the sensitivity of infected cells to TRAIL-mediated apoptosis. Down-modula tion 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 i dentify a mechanism for viral modulation of TRAIL receptor-mediated apoptos is and suggest the E3 protein complex has evolved to regulate the signaling of selected cytokine receptors.