Huang Bin, Seefelder Manuel, Buck Eva, Engler Tatjana, Lindenberg Katrin S, Klein Fabrice, Landwehrmeyer G Bernhard, Kochanek Stefan
Department of Gene Therapy, Ulm University, 89081 Ulm, Germany.
Department of Neurology, Ulm University, 89081 Ulm, Germany.
Neurobiol Dis. 2021 Oct;158:105476. doi: 10.1016/j.nbd.2021.105476. Epub 2021 Aug 12.
The huntingtin-associated protein 40 (HAP40) is an abundant interactor of huntingtin (HTT). In complexes of these proteins, HAP40 tightly binds to HTT in a cleft formed by two larger domains rich in HEAT repeats, and a smaller bridge domain connecting the two. We show that HAP40 steady-state protein levels are directly dependent on HTT (both normal and mutant HTT) and that HAP40 is strongly stabilized by the interaction with HTT resulting in an at least 5-fold increase in HAP40's half-life when bound to HTT. Cellular HAP40 protein levels were reduced in primary fibroblasts and lymphoblasts of Huntington Disease (HD) patients and in brain tissue of a full-length HTT mouse model of HD, concomitant with decreased soluble HTT levels in these cell types. This data and our previous demonstration of coevolution between HTT and HAP40 and evolutionary conservation of their interaction suggest that HAP40 is an obligate interaction partner of HTT. Our observation of reduced HAP40 levels in HD invites further studies, whether HAP40 loss-of-function contributes to the pathophysiology of HD.
亨廷顿蛋白相关蛋白40（HAP40）是亨廷顿蛋白（HTT）的一种丰富的相互作用蛋白。在这些蛋白质的复合物中，HAP40在由两个富含HEAT重复序列的较大结构域和连接两者的较小桥接结构域形成的裂隙中与HTT紧密结合。我们发现，HAP40的稳态蛋白水平直接依赖于HTT（正常和突变型HTT），并且HAP40通过与HTT的相互作用而得到强烈稳定，与HTT结合时HAP40的半衰期至少增加5倍。亨廷顿病（HD）患者的原代成纤维细胞和淋巴细胞以及HD全长HTT小鼠模型的脑组织中，细胞HAP40蛋白水平降低，同时这些细胞类型中可溶性HTT水平也降低。这些数据以及我们之前关于HTT和HAP40之间协同进化及其相互作用的进化保守性的证明表明，HAP40是HTT的一个必需相互作用伙伴。我们观察到HD中HAP40水平降低，这引发了进一步的研究，即HAP40功能丧失是否导致HD的病理生理学变化。
