自噬系统和蛋白酶体系统之间的相互联系

在真核细胞中已发现两条主要降解途径,即自噬系统和蛋白酶体系统．长期以来,这两条降解途径一直被认作是完全独立的路径,然而最近的证据强烈提示,这两条主要降解途径之间相互联系．其中,发现干扰这两条途径的任一条可影响另一条途径的活性,抑制蛋白酶体可刺激自噬活性．同时发现泛素的作用比先前想象更广泛,不仅具有标记蛋白酶体降解蛋白质这一 “经典作用”,还涉及自噬-溶酶体途径降解底物泛素化,是这些主要降解途径的共同标签．这些降解系统分享某些底物和调节分子,显示协同作用,在某些背景下,显示补偿功能．降解系统之间的协同和补偿作用在许多细胞过程中显得至关重要．因此这些降解系统异常或联系失常不仅导致细胞功能的异常,而且也与多种重要疾病的发生和发展密切相关．对这些降解途径功能及其联系的深入了解可拓展人们对这些降解途径的认识,有助于对多种细胞分解代谢过程的深入理解,也有助于相关新药的研发．     

泛素信号途径、自噬受体与细胞选择性自噬

蛋白质泛素化是真核生物细胞内蛋白质合成后最重要和最普遍的修饰方式之一。发生在蛋白质底物上的泛素化,由于其泛素化方式及形成泛素链的连接形式的多样性,又统称为泛素信号途径。研究表明,泛素信号途径对蛋白质的调节作用分为降解相关和非相关的两种。细胞内蛋白质的降解主要通过泛素-蛋白酶体或溶酶体-自噬途径来完成。一般认为,通过泛素-蛋白酶体降解的蛋白质具有很强的选择性,而通过溶酶体-自噬途径降解的蛋白质一般选择性较差。然而,近年来,细胞自噬受体如p62等的发现则表明细胞自噬同样具有很强的选择性,这一类由细胞自噬受体介导的细胞自噬被称为细胞选择性自噬(Selective autophagy)。蛋白质泛素化及降解调控几乎所有类型的细胞活动;与之对应的是,蛋白质泛素化及降解异常与包括肿瘤在内的多种人类疾病的发生发展密切相关。本文综述了泛素信号途径调控蛋白质通过蛋白酶体或自噬途径降解的基本过程和部分最新进展,并结合本实验室的研究成果介绍泛素化修饰细胞自噬受体调控细胞选择性自噬的新机制。     

自噬与泛素化蛋白降解途径的分子机制及其功能

细胞内所有的蛋白质和大多数的细胞外蛋白都在不断的进行更新,即它们在不断地被降解,并被新合成的蛋白质取代。细胞内蛋白的降解主要通过两个途径,即自噬和泛素蛋白酶体系统。自噬是一种由溶酶体介导的细胞内过多或异常蛋白质的降解机制。在细胞内主要有3种类型的自噬,即分子伴侣介导的自噬、微自噬和巨自噬。泛素蛋白酶体系统是由泛素介导的一种高度复杂的蛋白降解机制,它参与降解细胞内许多蛋白质并且这个过程具有高度特异性。细胞内蛋白质的降解参与调节许多细胞过程,包括细胞周期、DNA修复、细胞生长和分化、细胞质量的控制、病原生物的感染反应和细胞凋亡等。许多严重的人类疾病被认为是由于蛋白质降解系统的紊乱而引起的。文章综述了自噬和泛素化途径及其分子机制,以及蛋白质降解系统紊乱的病理学意义。     

自噬相关去泛素化酶及其小分子抑制剂的研究进展

自噬是进化上高度保守并受到多途径严密调控的细胞生物学过程,其向溶酶体递送多种细胞质组分以进行细胞内物质的降解以及再循环.这一过程涉及到细胞器的更新、错误折叠蛋白质和蛋白质聚集体以及细胞内病原体的清除.因此,自噬对于细胞稳态的维持至关重要,与许多人类疾病的发生发展密切相关.随着细胞自噬调节机制研究的不断深入,越来越多的去泛素化酶被证明在自噬相关的泛素信号调控系统中发挥了重要的作用.这些去泛素化酶作用于细胞自噬的不同阶段,靶向调节不同的泛素化自噬功能元件或自噬底物.去泛素化酶作为包括神经退行性疾病以及肿瘤在内的细胞自噬相关疾病的治疗靶点受到了广泛的关注,其中各类小分子抑制剂的发现为进一步研究去泛素化酶的自噬调节活性及相关疾病的治疗提供了可能.     

生物体内蛋白质降解系统的研究进展

生物体细胞内外多数的蛋白质处于极其稳定的动态平衡中,蛋白质的降解与合成是维持这种动态平衡的两种重要的代谢方式。胞内蛋白质的降解主要有两种途径:自噬和泛素-蛋白酶体系统。自噬是一种由溶酶体参与的对生物细胞内多余或异常蛋白质的降解途径,主要包括由分子伴侣介导的自噬、巨自噬和微自噬三种类型。泛素-蛋白酶体系统是一种非常复杂的蛋白质降解途径,具有高度的特异性,参与并调控细胞信号传递、免疫应答等绝大多数的生命活动。研究表明,多数疾病的发生与生物体内蛋白质的降级系统机能紊乱有关。因此,本文综述了生物体细胞内外蛋白质降解的两种途径及其机制,并总结了其病理学意义及研究进展。     

泛素-蛋白酶体途径的组成和功能

泛素-蛋白酶体途径是细胞内蛋白质选择性降解的重要途径,泛素分子主要通过泛素活化酶、泛素结合酶和泛素-蛋白连接酶与靶蛋白结合形成一条多泛素链,最后被26S蛋白酶体识别和降解。泛素-蛋白酶体途径参与细胞内的多种活动过程,包括细胞凋亡、MHCI类抗原的递呈、细胞周期以及细胞内信号转导,与细胞的一些生理功能和病理状态有着密切的联系。本文主要对组成泛素-蛋白酶体途径的各成分作一综述。     

泛素融合降解蛋白UFD1的结构与功能

泛素-蛋白酶体途径是细胞内蛋白质选择性降解的主要途径,参与多种真核生物细胞生理过程,与细胞的生理功能和病理状态有着密切的关系。该途径中UFD1作为泛素识别因子介导泛素化的靶蛋白至26S蛋白酶体降解。该文在概述泛素-蛋白酶体途径作用机制的基础上,对哺乳动物和酵母UFD1蛋白的结构及其在细胞周期调控、转录调控、内质网相关蛋白降解中的功能进行了综述。     

蛋白质的选择性降解机制——2004年诺贝尔化学奖部分工作介绍

如何识别和选择性降解蛋白质是细胞生命过程中的重要环节.泛素-蛋白酶体需能降解途径的发现,揭示了蛋白质在细胞内选择性降解的普遍方式.对于需要清除的蛋白质,通过其赖氨酸残基侧链ε-氨基连接多聚泛素链（降解标签）,继而在蛋白酶体中被降解.这种选择性降解机制对于维持蛋白质在细胞内含量的动态平衡起到了关键性作用.     

E3泛素连接酶接头蛋白Keap1的研究进展

Kelch样ECH关联蛋白1(Kelch-like ECH-associated protein 1,Keap1)是E3泛素连接酶的底物识别亚单位,在蛋白质的泛素化修饰中起重要作用.蛋白质的泛素化修饰作为一种重要且复杂的蛋白质翻译后修饰,在自噬和蛋白酶体系统中作为降解信号而被利用.野生型Keap1能够识别、结合多种底物...     

Interplay between autophagy and proteasome during protein turnover

Protein homeostasis is epitomized by an equilibrium between protein biosynthesis and degradation: the ‘life and death’ of proteins. Approximately one-third of newly synthesized proteins are degraded. As such, protein turnover is required to maintain cellular integrity and survival. Autophagy and the ubiquitin–proteasome system (UPS) are the two principal degradation pathways in eukaryotes. Both pathways orchestrate many cellular processes during development and upon environmental stimuli. Ubiquitination of degradation targets is used as a ‘death’ signal by both processes. Recent findings revealed a direct functional link between both pathways. Here, we summarize key findings in the field of protein homeostasis, with an emphasis on the newly revealed crosstalk between both degradation machineries and how it is decided which pathway facilitates target degradation.     

Phasing out the bad—How SQSTM1/p62 sequesters ubiquitinated proteins for degradation by autophagy

The degradation of misfolded, ubiquitinated proteins is essential for cellular homeostasis. These proteins are primarily degraded by the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy serves as a backup mechanism when the UPS is overloaded. How autophagy and the UPS are coordinated is not fully understood. During the autophagy of misfolded, ubiquitinated proteins, referred to as aggrephagy, substrate proteins are clustered into larger structures in a SQSTM1/p62-dependent manner before they are sequestered by phagophores, the precursors to autophagosomes. We have recently shown that SQSTM1/p62 and ubiquitinated proteins spontaneously phase separate into micrometer-sized clusters in vitro. This enabled us to characterize the properties of the ubiquitin-positive substrates that are necessary for the SQSTM1/p62-mediated cluster formation. Our results suggest that aggrephagy is triggered by the accumulation of substrates with multiple ubiquitin chains and that the process can be inhibited by active proteasomes.     

A novel link between autophagy and the ubiquitin-proteasome system

Autophagy and the ubiquitin-proteasome system (UPS) are the major routes for intracellular protein degradation. These two pathways were previously thought to be largely distinct. Here we summarize our recent work that demonstrates that long-term autophagy inhibition slows the clearance of short-lived UPS-specific substrates, like p53. This is caused by the accumulation of p62 after autophagy inhibition. These data suggest that the ramifications of a block in autophagy may be much wider than what was previously thought. Rather than simply decreasing clearance of autophagic substrates, while UPS flux is undisturbed, the cell will have to contend with a decrease in clearance by both major routes.     

Exosomes,autophagy and ER stress pathways in human diseases: Cross-regulation and therapeutic approaches

Exosomal release pathway and autophagy together maintain homeostasis and survival of cells under stressful conditions. Autophagy is a catabolic process through which cell entities, such as malformed biomacromolecules and damaged organelles, are degraded and recycled via the lysosomal-dependent pathway. Exosomes, a sub-type of extracellular vesicles (EVs) formed by the inward budding of multivesicular bodies (MVBs), are mostly involved in mediating communication between cells. The unfolded protein response (UPR) is an adaptive response that is activated to sustain survival in the cells faced with the endoplasmic reticulum (ER) stress through a complex network that involves protein synthesis, exosomes secretion and autophagy. Disruption of the critical crosstalk between EVs, UPR and autophagy may be implicated in various human diseases, including cancers and neurodegenerative diseases, yet the molecular mechanism(s) behind the coordination of these communication pathways remains obscure. Here, we review the available information on the mechanisms that control autophagy, ER stress and EV pathways, with the view that a better understanding of their crosstalk and balance may improve our knowledge on the pathogenesis and treatment of human diseases, where these pathways are dysregulated.     

Crosstalk between Endo/Exocytosis and Autophagy in Health and Disease

Imbalance between the main intracellular degradative, trafficking and intercellular shuttling pathways has been implicated in disease pathogenesis. Autophagy controls degradation of cellular components, while vesicular trafficking permits transport of material in and out of the cell. Emerging evidence has uncovered the extensive interconnectivity between these pathways, which is crucial to maintain organismal homeostasis. Thus, therapeutic intervention and drug development strategies targeting these processes, particularly in neurodegeneration, should account for this broad crosstalk, to maximize effectiveness. Here, recent findings underlining the highly dynamic nature of the crosstalk between autophagy, endosomal transport, and secretion is reviewed. Synergy of autophagy and endosomes for degradation, as well as, competition of autophagy and secretion are discussed. Perturbation of this crosstalk triggers pathology especially neurodegeneration.     

Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems

The ubiquitin proteasome system (UPS) and macroautophagy (hereafter called autophagy) were, for a long time, regarded as independent degradative pathways with few or no points of interaction. This view started to change recently, in the light of findings that have suggested that ubiquitylation can target substrates for degradation via both pathways. Moreover, perturbations in the flux through either pathway have been reported to affect the activity of the other system, and a number of mechanisms have been proposed to rationalise the link between the UPS and autophagy. Here we critically review these findings and outline some outstanding issues that still await clarification.     

Autophagy Coupling Interplay: Can Improve Cellular Repair and Aging?

Regular protein synthesis is a needful and complex task for a healthy cell. Improper folding leads to the deposition of misfolded proteins in cells. Autophagy and ubiquitin–proteasome system (UPS) are the conserved intracellular degradation processes of eukaryotic cells. How exactly these two pathways cross talk to each other is unclear. We do not know how the impairment of autophagy or UPS leads to the disturbance in cellular homeostasis and contribute into cellular aging and neurodegeneration. Here in this review, we will focus on the functional interconnections of autophagy and UPS, and why their loss of function results in abnormal aggregation of misfolded proteotoxic species in cells. Finally, we enumerate and discuss the crucial inducers of autophagy pathways and elaborate their intersection steps, which have been considered to be advantageous in aging linked with the abnormal protein aggregation. The final goal of this review is to improve our current understanding about multifaceted properties and interactions of autophagy and UPS, which may provide new insights to identify novel therapeutic strategies for aging and neurodegenerative diseases.