Alberti Simon, Mateju Daniel, Mediani Laura, Carra Serena
Alberti Lab, Max Planck Institute of Molecular Cell Biology and Genetics Dresden, Germany.
Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and Nanotechnology, University of Modena and Reggio Emilia Modena, Italy.
Front Mol Neurosci. 2017 Mar 27;10:84. doi: 10.3389/fnmol.2017.00084. eCollection 2017.
Ribonucleoprotein (RNP) granules transport, store, or degrade messenger RNAs, thereby indirectly regulating protein synthesis. Normally, RNP granules are highly dynamic compartments. However, because of aging or severe environmental stress, RNP granules, in particular stress granules (SGs), convert into solid, aggregate-like inclusions. There is increasing evidence that such RNA-protein inclusions are associated with several age-related neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), fronto-temporal dementia (FTD) and Alzheimer's disease (AD). Thus, understanding what triggers the conversion of RNP granules into aggregates and identifying the cellular players that control RNP granules will be critical to develop treatments for these diseases. In this review article, we discuss recent insight into RNP and SG formation. More specifically, we examine the evidence for liquid-liquid phase separation (LLPS) as an organizing principle of RNP granules and the role of aggregation-prone RNA-binding proteins (RBPs) in this process. We further discuss recent findings that liquid-like SGs can sequester misfolded proteins, which promote an aberrant conversion of liquid SGs into solid aggregates. Importantly, very recent studies show that a specific protein quality control (PQC) process prevents the accumulation of misfolding-prone proteins in SGs and, by doing so, maintains the dynamic state of SGs. This quality control process has been referred to as granulostasis and it relies on the specific action of the HSPB8-BAG3-HSP70 complex. Additional players such as p97/valosin containing protein (VCP) and other molecular chaperones (e.g., HSPB1) participate, directly or indirectly, in granulostasis, and ensure the timely elimination of defective ribosomal products and other misfolded proteins from SGs. Finally, we discuss recent findings that, in the stress recovery phase, SGs are preferentially disassembled with the assistance of chaperones, and we discuss evidence for a back-up system that targets aberrant SGs to the aggresome for autophagy-mediated clearance. Altogether the findings discussed here provide evidence for an intricate network of interactions between RNP granules and various components of the PQC machinery. Molecular chaperones in particular are emerging as key players that control the composition and dynamics of RNP granules, which may be important to protect against age-related diseases.
核糖核蛋白（RNP）颗粒可运输、储存或降解信使核糖核酸（mRNA），从而间接调节蛋白质合成。正常情况下，RNP颗粒是高度动态的区室。然而，由于衰老或严重的环境压力，RNP颗粒，特别是应激颗粒（SGs），会转变为固态的、类似聚集体的内含物。越来越多的证据表明，这种核糖核蛋白内含物与几种与年龄相关的神经退行性疾病有关，如肌萎缩侧索硬化症（ALS）、额颞叶痴呆（FTD）和阿尔茨海默病（AD）。因此，了解是什么触发RNP颗粒转变为聚集体以及确定控制RNP颗粒的细胞因子对于开发这些疾病的治疗方法至关重要。在这篇综述文章中，我们讨论了对RNP和SG形成的最新见解。更具体地说，我们研究了液-液相分离（LLPS）作为RNP颗粒组织原则的证据以及易聚集的核糖核酸结合蛋白（RBPs）在此过程中的作用。我们进一步讨论了最近的发现，即液态的SGs可以隔离错误折叠的蛋白质，这促进了液态SGs异常转变为固态聚集体。重要的是，最近的研究表明，一种特定的蛋白质质量控制（PQC）过程可防止易错误折叠的蛋白质在SGs中积累，从而维持SGs的动态状态。这种质量控制过程被称为颗粒稳态，它依赖于HSPB8 - BAG3 - HSP70复合物的特定作用。其他因子，如含缬酪肽蛋白（VCP）的p97和其他分子伴侣（如HSPB1）直接或间接参与颗粒稳态，并确保从SGs中及时清除有缺陷的核糖体产物和其他错误折叠的蛋白质。最后，我们讨论了最近的发现，即在应激恢复阶段，SGs在分子伴侣的协助下优先解体，并且我们讨论了一种将异常SGs靶向聚集体进行自噬介导清除的备用系统的证据。总之，这里讨论的发现为RNP颗粒与PQC机制的各种成分之间复杂的相互作用网络提供了证据。特别是分子伴侣正成为控制RNP颗粒组成和动态的关键因子，这对于预防与年龄相关的疾病可能很重要。
