Ramdzan Yasmin M, Trubetskov Mikhail M, Ormsby Angelique R, Newcombe Estella A, Sui Xiaojing, Tobin Mark J, Bongiovanni Marie N, Gras Sally L, Dewson Grant, Miller Jason M L, Finkbeiner Steven, Moily Nagaraj S, Niclis Jonathan, Parish Clare L, Purcell Anthony W, Baker Michael J, Wilce Jacqueline A, Waris Saboora, Stojanovski Diana, Böcking Till, Ang Ching-Seng, Ascher David B, Reid Gavin E, Hatters Danny M
Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
Australian Synchrotron, 800 Blackburn Road, Clayton, VIC 3168, Australia.
Cell Rep. 2017 May 2;19(5):919-927. doi: 10.1016/j.celrep.2017.04.029.
Competing models exist in the literature for the relationship between mutant Huntingtin exon 1 (Httex1) inclusion formation and toxicity. In one, inclusions are adaptive by sequestering the proteotoxicity of soluble Httex1. In the other, inclusions compromise cellular activity as a result of proteome co-aggregation. Using a biosensor of Httex1 conformation in mammalian cell models, we discovered a mechanism that reconciles these competing models. Newly formed inclusions were composed of disordered Httex1 and ribonucleoproteins. As inclusions matured, Httex1 reconfigured into amyloid, and other glutamine-rich and prion domain-containing proteins were recruited. Soluble Httex1 caused a hyperpolarized mitochondrial membrane potential, increased reactive oxygen species, and promoted apoptosis. Inclusion formation triggered a collapsed mitochondrial potential, cellular quiescence, and deactivated apoptosis. We propose a revised model where sequestration of soluble Httex1 inclusions can remove the trigger for apoptosis but also co-aggregate other proteins, which curtails cellular metabolism and leads to a slow death by necrosis.
文献中存在关于突变型亨廷顿蛋白外显子1（Httex1）包涵体形成与毒性之间关系的多种竞争模型。一种模型认为，包涵体通过隔离可溶性Httex1的蛋白毒性而具有适应性。另一种模型则认为，由于蛋白质组共聚集，包涵体会损害细胞活性。在哺乳动物细胞模型中，我们使用一种Httex1构象生物传感器，发现了一种能够协调这些相互竞争模型的机制。新形成的包涵体由无序的Httex1和核糖核蛋白组成。随着包涵体的成熟，Httex1重新配置为淀粉样蛋白，并招募了其他富含谷氨酰胺和含朊病毒结构域的蛋白质。可溶性Httex1导致线粒体膜电位超极化、活性氧增加，并促进细胞凋亡。包涵体的形成引发线粒体电位崩溃、细胞静止，并使细胞凋亡失活。我们提出了一个修订模型，其中可溶性Httex1包涵体的隔离可以消除细胞凋亡的触发因素，但也会使其他蛋白质共聚集，从而抑制细胞代谢并导致坏死性缓慢死亡。
