Perturbation of Huntingtin (HTT) physiological function is one postulated pathogenic factor in Huntington disease (HD). However, little is known how HTT is regulated in vivo. In a proteomic study, we isolated a novel ~40kDa protein as a strong binding partner of Drosophila HTT and demonstrated it was the functional ortholog of HAP40, an HTT associated protein shown recently to modulate HTT conformation but with unclear physiological and pathologic roles. We showed that in both flies and human cells, HAP40 maintained conserved physical and functional interactions with HTT, loss of HAP40 resulted in similar phenotypes as HTT knockout, including animal viability and autophagy, and more strikingly, HAP40 depletion significantly reduced the levels of endogenous HTT, while HAP40 was mostly degraded via the proteasome in the absence of HTT. Interestingly, polyglutamine expansion in HTT did not affect its affinity for HAP40. However, HAP40 modulated HD pathogenesis in Drosophila model by regulating the overall protein levels and the toxicity of full-length mutant HTT. Together, our study uncovers a conserved mechanism governing the stability and in vivo functions of HTT, and demonstrates that HAP40 is a central and positive regulator of HTT, a potential modulator of HD pathogenesis and a promising candidate for HTT-lowering strategy against HD.

中文翻译：

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HAP40是亨廷顿蛋白的保守中央调节剂，是突变亨廷顿蛋白毒性的特定调节剂

亨廷顿病（HTT）生理功能的扰动是亨廷顿病（HD）中一种假定的致病因素。但是，鲜为人知如何在体内调节HTT。在蛋白质组学研究中，我们分离出一种新的〜40kDa蛋白作为果蝇HTT的强结合伴侣，并证明它是HAP40的功能直系同源物，HAP40是一种最近与HTT相关的蛋白，可调节HTT构象，但其生理和病理作用尚不清楚。我们表明，在果蝇和人细胞中，HAP40都与HTT保持了保守的物理和功能相互作用，HAP40的丧失导致了与HTT基因敲除相似的表型，包括动物生存力和自噬，而且更惊人的是，HAP40的消耗显着降低了内源性HTT的水平，而在没有HTT的情况下，HAP40主要通过蛋白酶体降解。有趣的是 HTT中的聚谷氨酰胺扩展不会影响其对HAP40的亲和力。但是，HAP40通过调节总蛋白水平和全长突变型HTT的毒性来调节果蝇模型的HD发病机理。总之，我们的研究揭示了控制HTT稳定性和体内功能的保守机制，并证明HAP40是HTT的核心和正向调节剂，是HD发病机理的潜在调节剂，并且是针对HD的HTT降低策略的有希望的候选者。