Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Prog Mol Subcell Biol. 2021;59:115-143. doi: 10.1007/978-3-030-67696-4_6.
Protein aggregation is now a common hallmark of numerous human diseases, most of which involve cytosolic aggregates including Aβ (AD) and ⍺-synuclein (PD) in Alzheimer's disease and Parkinson's disease. However, it is also evident that protein aggregation can also occur in the lumen of the endoplasmic reticulum (ER) that leads to specific diseases due to loss of protein function or detrimental effects on the host cell, the former is inherited in a recessive manner where the latter are dominantly inherited. However, the mechanisms of protein aggregation, disaggregation and degradation in the ER are not well understood. Here we provide an overview of factors that cause protein aggregation in the ER and how the ER handles aggregated proteins. Protein aggregation in the ER can result from intrinsic properties of the protein (hydrophobic residues in the ER), oxidative stress or nutrient depletion. The ER has quality control mechanisms [chaperone functions, ER-associated protein degradation (ERAD) and autophagy] to ensure only correctly folded proteins exit the ER and enter the cis-Golgi compartment. Perturbation of protein folding in the ER activates the unfolded protein response (UPR) that evolved to increase ER protein folding capacity and efficiency and degrade misfolded proteins. Accumulation of misfolded proteins in the ER to a level that exceeds the ER-chaperone folding capacity is a major factor that exacerbates protein aggregation. The most significant ER resident protein that prevents protein aggregation in the ER is the heat shock protein 70 (HSP70) homologue, BiP/GRP78, which is a peptide-dependent ATPase that binds unfolded/misfolded proteins and releases them upon ATP binding. Since exogenous factors can also reduce protein misfolding and aggregation in the ER, such as chemical chaperones and antioxidants, these treatments have potential therapeutic benefit for ER protein aggregation-associated diseases.
蛋白质聚集现在是许多人类疾病的共同标志，其中大多数涉及细胞质聚集物，包括阿尔茨海默病和帕金森病中的 Aβ（AD）和 ⍺-突触核蛋白（PD）。然而，很明显，蛋白质聚集也可能发生在内质网（ER）的腔中，由于蛋白质功能丧失或对宿主细胞产生不利影响而导致特定疾病，前者以隐性方式遗传，后者以显性方式遗传。然而，内质网中蛋白质聚集、解聚和降解的机制尚未得到很好的理解。在这里，我们提供了一个概述，介绍内质网中导致蛋白质聚集的因素以及内质网如何处理聚集的蛋白质。内质网中蛋白质的聚集可能是由于蛋白质的固有性质（内质网中的疏水残基）、氧化应激或营养物质耗竭引起的。内质网具有质量控制机制[伴侣功能、内质网相关蛋白降解（ERAD）和自噬]，以确保只有正确折叠的蛋白质离开内质网并进入顺式高尔基体隔室。内质网中蛋白质折叠的扰动会激活未折叠蛋白反应（UPR），这一反应的进化是为了增加内质网的蛋白质折叠能力和效率，并降解错误折叠的蛋白质。内质网中错误折叠蛋白质的积累超过内质网伴侣的折叠能力是加剧蛋白质聚集的一个主要因素。防止内质网中蛋白质聚集的最重要的内质网驻留蛋白是热休克蛋白 70（HSP70）同源物 BiP/GRP78，它是一种肽依赖性 ATP 酶，可结合未折叠/错误折叠的蛋白质，并在结合 ATP 时释放它们。由于外源性因素也可以减少内质网中蛋白质的错误折叠和聚集，如化学伴侣和抗氧化剂，这些治疗方法对内质网蛋白聚集相关疾病具有潜在的治疗益处。
