Eisenack Tom Joshua, Trentini Débora Broch
University of Cologne, Faculty of Medicine, University Hospital of Cologne, Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Front Mol Biosci. 2023 Jan 4;9:1089825. doi: 10.3389/fmolb.2022.1089825. eCollection 2022.
Proteins are versatile molecular machines that control and execute virtually all cellular processes. They are synthesized in a multilayered process requiring transfer of information from DNA to RNA and finally into polypeptide, with many opportunities for error. In addition, nascent proteins must successfully navigate a complex folding-energy landscape, in which their functional native state represents one of many possible outcomes. Consequently, newly synthesized proteins are at increased risk of misfolding and toxic aggregation. To maintain proteostasis-the state of proteome balance-cells employ a plethora of molecular chaperones that guide proteins along a productive folding pathway and quality control factors that direct misfolded species for degradation. Achieving the correct balance between folding and degradation therefore represents a fundamental task for the proteostasis network. While many chaperones act co-translationally, protein quality control is generally considered to be a post-translational process, as the majority of proteins will only achieve their final native state once translation is completed. Nevertheless, it has been observed that proteins can be ubiquitinated during synthesis. The extent and the relevance of co-translational protein degradation, as well as the underlying molecular mechanisms, remain areas of open investigation. Recent studies made seminal advances in elucidating ribosome-associated quality control processes, and how their loss of function can lead to proteostasis failure and disease. Here, we discuss current understanding of the situations leading to the marking of nascent proteins for degradation before synthesis is completed, and the emerging quality controls pathways engaged in this task in eukaryotic cells. We also highlight the methods used to study co-translational quality control.
蛋白质是多功能的分子机器，几乎控制和执行所有细胞过程。它们通过一个多层过程合成，该过程需要将信息从DNA传递到RNA，最终传递到多肽，在此过程中有很多出错的机会。此外，新生蛋白质必须成功穿越复杂的折叠能量景观，其中它们的功能性天然状态只是众多可能结果之一。因此，新合成的蛋白质发生错误折叠和有毒聚集的风险增加。为了维持蛋白质稳态——蛋白质组平衡的状态——细胞利用大量分子伴侣来引导蛋白质沿着一条有效的折叠途径进行折叠，并利用质量控制因子来引导错误折叠的蛋白质进行降解。因此，在折叠和降解之间实现正确的平衡是蛋白质稳态网络的一项基本任务。虽然许多分子伴侣在共翻译过程中发挥作用，但蛋白质质量控制通常被认为是一个翻译后过程，因为大多数蛋白质只有在翻译完成后才会达到其最终的天然状态。然而，人们已经观察到蛋白质在合成过程中可以被泛素化。共翻译蛋白质降解的程度和相关性，以及潜在的分子机制，仍然是有待深入研究的领域。最近的研究在阐明核糖体相关的质量控制过程以及它们的功能丧失如何导致蛋白质稳态失衡和疾病方面取得了重大进展。在这里，我们讨论了目前对在合成完成前导致新生蛋白质被标记进行降解的情况的理解，以及真核细胞中参与这项任务的新出现的质量控制途径。我们还强调了用于研究共翻译质量控制的方法。
