Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA.
Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD, USA.
FEBS J. 2022 Oct;289(20):6132-6153. doi: 10.1111/febs.16129. Epub 2021 Jul 28.
Ubiquilin (UBQLN) proteins are a dynamic and versatile family of proteins found in all eukaryotes that function in the regulation of proteostasis. Besides their canonical function as shuttle factors in delivering misfolded proteins to the proteasome and autophagy systems for degradation, there is emerging evidence that UBQLN proteins play broader roles in proteostasis. New information suggests the proteins function as chaperones in protein folding, protecting proteins prior to membrane insertion, and as guardians for mitochondrial protein import. In this review, we describe the evidence for these different roles, highlighting how different domains of the proteins impart these functions. We also describe how changes in the structure and phase separation properties of UBQLNs may regulate their activity and function. Finally, we discuss the pathogenic mechanisms by which mutations in UBQLN2 cause amyotrophic lateral sclerosis and frontotemporal dementia. We describe the animal model systems made for different UBQLN2 mutations and how lessons learnt from these systems provide fundamental insight into the molecular mechanisms by which UBQLN2 mutations drive disease pathogenesis through disturbances in proteostasis.
泛素结合酶 11（UBQLN）蛋白是一类在所有真核生物中均存在的、具有动态性和多功能性的蛋白家族，其功能在于调控蛋白稳态。除了作为将错误折叠蛋白递送至蛋白酶体和自噬系统进行降解的穿梭因子的经典功能外，越来越多的证据表明 UBQLN 蛋白在蛋白稳态中发挥着更广泛的作用。新信息表明，这些蛋白在蛋白折叠过程中充当伴侣，在蛋白质插入膜之前对其进行保护，并作为线粒体蛋白输入的守护者。在这篇综述中，我们描述了这些不同作用的证据，强调了蛋白不同结构域赋予这些功能的方式。我们还描述了 UBQLN 结构和相分离特性的变化如何调节其活性和功能。最后，我们讨论了 UBQLN2 突变导致肌萎缩侧索硬化症和额颞叶痴呆的发病机制。我们描述了针对不同 UBQLN2 突变的动物模型系统，以及从这些系统中获得的经验教训如何为理解 UBQLN2 突变通过扰乱蛋白稳态导致疾病发病机制的分子机制提供了基本的见解。
