Protein misfolding is a major driver of ageing-associated frailty and disease pathology. Although all cells possess multiple, well-characterised protein quality control systems to mitigate the toxicity of misfolded proteins, how they are integrated to maintain protein homeostasis (‘proteostasis’) in health—and how their disintegration contributes to disease—is still an exciting and fast-paced area of research. Under physiological conditions, the predominant route for misfolded protein clearance involves ubiquitylation and proteasome-mediated degradation. When the capacity of this route is overwhelmed—as happens during conditions of acute environmental stress, or chronic ageing-related decline—alternative routes for protein quality control are activated. In this review, we summarise our current understanding of how proteasome-targeted misfolded proteins are retrafficked to alternative protein quality control routes such as juxta-nuclear sequestration and selective autophagy when the ubiquitin–proteasome system is compromised. We also discuss the molecular determinants of these alternative protein quality control systems, attempt to clarify distinctions between various cytoplasmic spatial quality control inclusion bodies (e.g., Q-bodies, p62 bodies, JUNQ, aggresomes, and aggresome-like induced structures ‘ALIS’), and speculate on emerging concepts in the field that we hope will spur future research—with the potential to benefit the rational development of healthy ageing strategies.

中文翻译：

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错误折叠蛋白清除的替代系统：蛋白酶体之外的生命

蛋白质错误折叠是衰老相关虚弱和疾病病理学的主要驱动因素。尽管所有细胞都拥有多个、特征明确的蛋白质质量控​​制系统来减轻错误折叠蛋白质的毒性，但它们如何整合以维持健康的蛋白质稳态（“蛋白质稳态”）——以及它们的分解如何导致疾病——仍然是一个令人兴奋的问题。快节奏的研究领域。在生理条件下，错误折叠蛋白清除的主要途径涉及泛素化和蛋白酶体介导的降解。当这条途径的能力不堪重负时——如在急性环境压力或慢性衰老相关衰退期间发生的情况——蛋白质质量控​​制的替代途径被激活。在这次审查中，我们总结了我们目前对蛋白酶体靶向错误折叠蛋白质如何在泛素 - 蛋白酶体系统受损时重新分配到替代蛋白质质量控​​制途径的理解，例如近核隔离和选择性自噬。我们还讨论了这些替代蛋白质质量控​​制系统的分子决定因素，试图阐明各种细胞质空间质量控制包涵体（例如 Q 体、p62 体、JUNQ、aggresomes 和类聚合体诱导结构 'ALIS'）之间的区别，并推测该领域的新兴概念，我们希望这些概念将刺激未来的研究——有可能有利于健康老龄化策略的合理发展。