Wu Shuangcheng Alivia, Li Zexin Jason, Qi Ling
Department of Molecular Physiology and Biological Physics, University of Virginia, School of Medicine, Charlottesville, VA 22903, USA.
Department of Molecular Physiology and Biological Physics, University of Virginia, School of Medicine, Charlottesville, VA 22903, USA; Medical Scientist Training Program, University of Virginia, School of Medicine, Charlottesville, VA 22903, USA.
Trends Cell Biol. 2025 Jul;35(7):576-591. doi: 10.1016/j.tcb.2025.01.002. Epub 2025 Feb 4.
Protein misfolding and aggregation in the endoplasmic reticulum (ER) have been causally linked to a variety of human diseases. Two key pathways for eliminating misfolded proteins and aggregates in the ER are ER-associated degradation (ERAD) and ER-phagy, respectively. While both pathways have been well characterized biochemically, our understanding of their physiological relevance and significance remains limited. In recent years, significant advances have been made, including the generation and characterization of various knockout and knockin mouse models, the identification of human disease-associated or -causing variants, and insights into the coordination between ERAD and autophagy in physiological contexts. In this review, we summarize these advancements, highlighting the key roles of a highly conserved suppressor of lin-12-like-hydroxymethyl glutaryl-coenzyme A reductase degradation 1 (SEL1L-HRD1) protein complex of ERAD and ER-phagy in health and disease.
内质网（ER）中的蛋白质错误折叠和聚集与多种人类疾病存在因果关系。在内质网中消除错误折叠蛋白质和聚集体的两个关键途径分别是内质网相关降解（ERAD）和内质网自噬。虽然这两个途径在生物化学方面都已得到充分表征，但我们对它们的生理相关性和重要性的理解仍然有限。近年来取得了重大进展，包括各种基因敲除和基因敲入小鼠模型的建立和表征、人类疾病相关或致病变体的鉴定，以及对生理环境中ERAD和自噬之间协调作用的深入了解。在这篇综述中，我们总结了这些进展，强调了内质网相关降解和内质网自噬中高度保守的类lin-12样-羟甲基戊二酰辅酶A还原酶降解抑制因子1（SEL1L-HRD1）蛋白复合物在健康和疾病中的关键作用。
