Benedict C A, Norris P S, Prigozy T I, Bodmer J L, Mahr J A, Garnett C T, Martinon F, Tschopp J, Gooding L R, Ware C F
Division of Molecular Immunology and the Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
J Biol Chem. 2001 Feb 2;276(5):3270-8. doi: 10.1074/jbc.M008218200. Epub 2000 Oct 24.
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.
腺病毒编码多种基因产物，这些产物可调节由先天免疫系统和适应性免疫系统介导的针对病毒感染的促凋亡细胞反应。已知E3 - 10.4K和14.5K基因产物可调节死亡受体Fas。在本研究中，我们证明腺病毒的另一种E3蛋白6.7K在特异性调节肿瘤坏死因子相关凋亡诱导配体（TRAIL）的两种死亡受体中发挥作用。6.7K蛋白在细胞表面表达，并与10.4K和14.5K蛋白形成复合物，该复合物足以诱导TRAIL受体-1和-2从细胞表面下调，并逆转受感染细胞对TRAIL介导的凋亡的敏感性。E3复合物对TRAIL - R2的下调依赖于受体的细胞质尾巴，但仅死亡结构域是不够的。这些结果确定了病毒调节TRAIL受体介导的凋亡的机制，并表明E3蛋白复合物已经进化以调节选定细胞因子受体的信号传导。
