Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA; email:
Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat-Ram, Jerusalem 91904, Israel; email:
Annu Rev Biochem. 2018 Jun 20;87:725-749. doi: 10.1146/annurev-biochem-062917-012730.
Nuclear proteins participate in diverse cellular processes, many of which are essential for cell survival and viability. To maintain optimal nuclear physiology, the cell employs the ubiquitin-proteasome system to eliminate damaged and misfolded proteins in the nucleus that could otherwise harm the cell. In this review, we highlight the current knowledge about the major ubiquitin-protein ligases involved in protein quality control degradation (PQCD) in the nucleus and how they orchestrate their functions to eliminate misfolded proteins in different nuclear subcompartments. Many human disorders are causally linked to protein misfolding in the nucleus, hence we discuss major concepts that still need to be clarified to better understand the basis of the nuclear misfolded proteins' toxic effects. Additionally, we touch upon potential strategies for manipulating nuclear PQCD pathways to ameliorate diseases associated with protein misfolding and aggregation in the nucleus.
核蛋白参与多种细胞过程，其中许多过程对于细胞的存活和活力至关重要。为了维持最佳的核生理功能，细胞利用泛素-蛋白酶体系统来清除细胞核中受损和错误折叠的蛋白质，否则这些蛋白质可能会对细胞造成伤害。在这篇综述中，我们强调了目前关于参与核内蛋白质质量控制降解（PQCD）的主要泛素-蛋白连接酶的知识，以及它们如何协调其功能以消除不同核亚区中错误折叠的蛋白质。许多人类疾病与核内蛋白质错误折叠有关，因此我们讨论了仍需要澄清的主要概念，以更好地理解核内错误折叠蛋白质毒性作用的基础。此外，我们还探讨了操纵核 PQCD 途径的潜在策略，以改善与核内蛋白质错误折叠和聚集相关的疾病。
