Zhao Ling-Jun, Loewenstein Paul M, Green Maurice
Department of Microbiology and Molecular Immunology/Institute for Molecular Virology, Saint Louis University School of Medicine, Doisy Research Center, St. Louis, MO 63104, USA.
Department of Microbiology and Molecular Immunology/Institute for Molecular Virology, Saint Louis University School of Medicine, Doisy Research Center, St. Louis, MO 63104, USA.
Virology. 2016 Dec;499:178-184. doi: 10.1016/j.virol.2016.09.005. Epub 2016 Sep 22.
The adenovirus E1A 243R oncoprotein targets TRRAP, a scaffold protein that assembles histone acetyltransferase (HAT) complexes, such as the NuA4/Tip60 complex which mediates transcriptional activity of the proto-oncogene MYC and helps determine the cancer cell phenotype. How E1A transforms cells through TRRAP remains obscure. We performed proteomic analysis with the N-terminal transcriptional repression domain of E1A 243R (E1A 1-80) and showed that E1A 1-80 interacts with TRRAP, p400, and three other members of the NuA4 complex - DMAP1, RUVBL1 and RUVBL2 - not previously shown to associate with E1A 243R. E1A 1-80 interacts with these NuA4 components and MYC through the E1A TRRAP-targeting domain. E1A 243R association with the NuA4 complex was demonstrated by co-immunoprecipitation and analysis with DMAP1, Tip60, and MYC. Significantly, E1A 243R promotes association of MYC/MAX with the NuA4/Tip60 complex, implicating the importance of the MYC/NuA4 pathway in cellular transformation by both MYC and E1A.
腺病毒E1A 243R癌蛋白作用于TRRAP，TRRAP是一种组装组蛋白乙酰转移酶（HAT）复合物的支架蛋白，如介导原癌基因MYC转录活性并有助于确定癌细胞表型的NuA4/Tip60复合物。E1A如何通过TRRAP转化细胞仍不清楚。我们用E1A 243R的N端转录抑制结构域（E1A 1-80）进行了蛋白质组学分析，结果表明E1A 1-80与TRRAP、p400以及NuA4复合物的其他三个成员——DMAP1、RUVBL1和RUVBL2相互作用，此前未发现它们与E1A 243R相关联。E1A 1-80通过E1A的TRRAP靶向结构域与这些NuA4组分和MYC相互作用。通过与DMAP1、Tip60和MYC的共免疫沉淀和分析，证实了E1A 243R与NuA4复合物的关联。重要的是，E1A 243R促进了MYC/MAX与NuA4/Tip60复合物的结合，这表明MYC/NuA4途径在MYC和E1A介导的细胞转化中具有重要作用。
