Martinet Wim, Agostinis Patrizia, Vanhoecke Barbara, Dewaele Michael, De Meyer Guido R Y
Division of Pharmacology, University of Antwerp, B-2610 Antwerp, Belgium.
Clin Sci (Lond). 2009 May;116(9):697-712. doi: 10.1042/CS20080508.
Autophagy is a catabolic trafficking pathway for bulk destruction and turnover of long-lived proteins and organelles via regulated lysosomal degradation. In eukaryotic cells, autophagy occurs constitutively at low levels to perform housekeeping functions, such as the destruction of dysfunctional organelles. Up-regulation occurs in the presence of external stressors (e.g. starvation, hormonal imbalance and oxidative stress) and internal needs (e.g. removal of protein aggregates), suggesting that the process is an important survival mechanism. However, the occurrence of autophagic structures in dying cells of different organisms has led to the hypothesis that autophagy may also have a causative role in stress-induced cell death. The identification within the last decade of a full set of genes essential for autophagy in yeast, the discovery of human orthologues and the definition of signalling pathways regulating autophagy have accelerated our molecular understanding and interest in this fundamental process. A growing body of evidence indicates that autophagy is associated with heart disease, cancer and a number of neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases. Furthermore, it has been demonstrated that autophagy plays a role in embryogenesis, aging and immunity. Recently, it has been shown that autophagy can be intensified by specific drugs. The pharmacological modulation of the autophagic pathway represents a major challenge for clinicians to treat human disease.
自噬是一种分解代谢的运输途径，通过受调控的溶酶体降解对长寿蛋白和细胞器进行大量破坏和更新。在真核细胞中，自噬以低水平持续发生，以执行维持细胞内环境稳定的功能，如破坏功能失调的细胞器。在存在外部应激源（如饥饿、激素失衡和氧化应激）和内部需求（如清除蛋白质聚集体）时，自噬会上调，这表明该过程是一种重要的生存机制。然而，在不同生物体的濒死细胞中出现自噬结构，引发了一种假说，即自噬可能在应激诱导的细胞死亡中也具有因果作用。在过去十年中，酵母中自噬所需全套基因的鉴定、人类同源物的发现以及调节自噬的信号通路的定义，加速了我们对这一基本过程的分子理解和兴趣。越来越多的证据表明，自噬与心脏病、癌症以及一些神经退行性疾病有关，如阿尔茨海默病、帕金森病和亨廷顿舞蹈症。此外，已经证明自噬在胚胎发生、衰老和免疫中发挥作用。最近，研究表明特定药物可以增强自噬。自噬途径的药理学调节对临床医生治疗人类疾病来说是一项重大挑战。
