Protein homeostasis (proteostasis) is essential for the cell and is maintained by a highly conserved protein quality control (PQC) system, which triages newly synthesized, mislocalized and misfolded proteins. The ubiquitin-proteasome system (UPS), molecular chaperones, and co-chaperones are vital PQC elements that work together to facilitate degradation of misfolded and toxic protein species through the 26S proteasome. However, the underlying mechanisms are complex and remain partly unclear. Here, we provide an overview of the current knowledge on the co-chaperones that directly take part in targeting and delivery of PQC substrates for degradation. While J-domain proteins (JDPs) target substrates for the heat shock protein 70 (HSP70) chaperones, nucleotide-exchange factors (NEFs) deliver HSP70-bound substrates to the proteasome. So far, three NEFs have been established in proteasomal delivery: HSP110 and the ubiquitin-like (UBL) domain proteins BAG-1 and BAG-6, the latter acting as a chaperone itself and carrying its substrates directly to the proteasome. A better understanding of the individual delivery pathways will improve our ability to regulate the triage, and thus regulate the fate of aberrant proteins involved in cell stress and disease, examples of which are given throughout the review.

中文翻译：

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将错误折叠蛋白靶向并递送至 26S 蛋白酶体的共伴侣。


蛋白质稳态（蛋白质稳态）对于细胞至关重要，并由高度保守的蛋白质质量控​​制 (PQC) 系统维持，该系统对新合成、错误定位和错误折叠的蛋白质进行分类。泛素-蛋白酶体系统 (UPS)、分子伴侣和辅助伴侣是重要的 PQC 元件，它们共同作用，促进通过 26S 蛋白酶体降解错误折叠和有毒的蛋白质种类。然而，潜在的机制很复杂，并且部分尚不清楚。在这里，我们概述了直接参与 PQC 底物降解的靶向和递送的共伴侣的当前知识。 J 结构域蛋白 (JDP) 靶向热休克蛋白 70 (HSP70) 伴侣的底物，而核苷酸交换因子 (NEF) 将 HSP70 结合底物传递至蛋白酶体。到目前为止，在蛋白酶体递送中已经建立了三种 NEF：HSP110 和泛素样 (UBL) 结构域蛋白 BAG-1 和 BAG-6，后者本身充当伴侣，并将其底物直接携带至蛋白酶体。更好地了解个体传递途径将提高我们调节分类的能力，从而调节与细胞应激和疾病有关的异常蛋白的命运，整个综述中给出了一些例子。