Department of Biological Sciences, Hampton University, Hampton, VA 23668, United States.
Mol Cell Endocrinol. 2011 Jan 30;332(1-2):196-212. doi: 10.1016/j.mce.2010.10.012. Epub 2010 Nov 12.
Aggresome formation, a cellular response to misfolded protein aggregates, is linked to cancer and neurodegenerative disorders. Previously we showed that Gag-v-ErbA (v-ErbA), a retroviral variant of the thyroid hormone receptor (TRα1), accumulates in and sequesters TRα1 into cytoplasmic foci. Here, we show that foci represent v-ErbA targeting to aggresomes. v-ErbA colocalizes with aggresomal markers, proteasomes, hsp70, HDAC6, and mitochondria. Foci have hallmark characteristics of aggresomes: formation is microtubule-dependent, accelerated by proteasome inhibitors, and they disrupt intermediate filaments. Proteasome-mediated degradation is critical for clearance of v-ErbA and T(3)-dependent TRα1 clearance. Our studies highlight v-ErbA's complex mode of action: the oncoprotein is highly mobile and trafficks between the nucleus, cytoplasm, and aggresome, carrying out distinct activities within each compartment. Dynamic trafficking to aggresomes contributes to the dominant negative activity of v-ErbA and may be enhanced by the viral Gag sequence. These studies provide insight into novel modes of oncogenesis across multiple cellular compartments.
聚集物形成是细胞对错误折叠蛋白聚集的一种反应,与癌症和神经退行性疾病有关。之前我们发现,Gag-v-ErbA(v-ErbA),一种甲状腺激素受体(TRα1)的逆转录病毒变体,会在细胞质中积累并将 TRα1 隔离到细胞内的焦点中。在这里,我们表明焦点代表 v-ErbA 靶向聚集物。v-ErbA 与聚集物标记物、蛋白酶体、hsp70、HDAC6 和线粒体共定位。焦点具有聚集物的标志性特征:形成依赖微管,被蛋白酶体抑制剂加速,它们破坏中间丝。蛋白酶体介导的降解对于清除 v-ErbA 和 T(3)依赖性 TRα1 清除至关重要。我们的研究强调了 v-ErbA 的复杂作用模式:这种癌蛋白具有高度的流动性,在核、细胞质和聚集物之间穿梭,在每个隔室中执行不同的活性。动态运输到聚集物有助于 v-ErbA 的显性负活性,并且可能被病毒 Gag 序列增强。这些研究为跨多个细胞隔室的新型致癌模式提供了深入了解。