细胞自噬的调控与自噬程序性死亡的研究进展

自噬(autophagy)是一种溶酶体依赖性降解途径,涉及细胞内长寿蛋白和受损伤细胞器的降解,其既是细胞保守的自我防御机制,又是一种程序性细胞死亡机制(PCD),与机体的多种疾病有密切关系.自噬具有独特的形态改变和特有的调控通路,自噬的调控涉及到多种机制、如翻译后修饰等.凋亡是研究最清楚的程序性细胞死亡机制,凋亡与细胞自噬程序性死亡之间存在着复杂的关系.对哺乳动物细胞自噬的分子调控机制,自噬程序性细胞死亡过程及其与凋亡的关系等方面进行探讨很有意义.     

细胞自噬的形态学特征和功能意义

目的 自噬是细胞受到刺激后吞噬自身的细胞质或细胞器,最终将吞噬物在溶酶体内降解的过程.按吞噬物进入溶酶体的途径,自噬可分为巨自噬、微自噬和分子伴侣介导的自噬3类.在巨自噬,自噬前体包裹细胞质或细胞器后形成自噬体,继而自噬体与溶酶体结合形成自噬溶酶体,自噬体内容物被降解.在微自噬,溶酶体膜凹陷,直接吞噬细胞质、细胞器或细胞核,形成自噬体,然后被溶酶体酶降解.分子伴侣介导的自噬是通过溶酶体膜的受体将细胞质内的蛋白质转运入溶酶体.自噬从酵母至哺乳动物细胞均很保守,对于耐受饥饿和缺血,清除衰老细胞器,清除细菌和异物,维持细胞活性和延长寿命等起着重要作用.自噬活动受自噬基因的调控,自噬基因缺失或功能障碍时可导致某些疾病的发生.深入认识自噬过程以及由此产生的自噬体等结构及其功能有助于探讨自噬对于人体生理和病理作用的机制.本文综述了自噬的形态学特征及其功能意义.     

自噬调控在淋巴瘤中的研究进展

自噬是一种多步骤溶酶体降解途径,一方面对稳态维持至关重要,另一方面又与多种疾病的发生、发展有关。这个过程受到复杂的网络调控,主要包括mTOR依赖的信号通路,和其他如与Ca~(2+)、活性氧、RNA、表观遗传、翻译机制等相关的调控途径。细胞自噬与淋巴瘤的发生发展密切相关,目前研究发现在淋巴瘤中存在多种途径参与自噬的调控,该文主要阐述细胞自噬调控途径及在淋巴瘤中的研究进展。     

自噬与固有免疫应答相互调节研究进展

自噬在细胞分化、肿瘤、炎症、免疫等多方面发挥关键作用.近年来,随着分子生物学、细胞生物学、免疫学等学科的发展,研究发现细胞自噬与固有免疫应答有着重要的相互调控作用.自噬是固有免疫的重要组成成分,可以通过溶酶体直接降解被自噬体包裹的病原体.自噬参与众多固有免疫信号的调控.固有免疫信号也诱导或抑制自噬.自噬在抗胞内病原体感染中发挥重要作用.     

细胞自噬:病理学研究的新热点

自噬(autophagy)是真核细胞中一种普遍而又重要的生命现象,其主要作用是清除和降解自身受损的细胞器以及多余的生物大分子,并利用降解产物提供能量和重建细胞结构,在维持细胞稳态和细胞生命活动等方面起重要作用.本文就近年来在自噬过程、自噬信号转导途径以及自噬的分子机制和调控机制、自噬与细胞生存、凋亡和肿瘤等方面取得的一些进展进行综述.     

细胞自噬机制开启疾病治疗新途径

自噬是指细胞内细胞器和蛋白质等在溶酶体被降解及其降解产物被重新利用的过程。日本科学家大隅良典(Yoshinori Ohsumi)发现了15个自噬相关基因并阐述了自噬机制,获得2016年诺贝尔生理学与医学奖。他的开创性研究成果为探讨细胞自噬的生理和病理作用奠定了重要基础,并为通过调节细胞自噬治疗疾病开辟了新途径。自噬是一种普遍性细胞反应,正常情况下细胞自噬水平很低,受生理或病理性刺激后自噬水平显著升高。自噬相关基因缺失或自噬功能障碍时可导致某些疾病的发生。近来,人们试图通过激活或抑制细胞自噬预防和治疗自噬障碍相关性疾病。     

自噬与p62/SQSTM1在肝缺血再灌注中的作用

自噬是溶酶体依赖性的降解系统,p62作为重要的蛋白载体,可促进受损蛋白经蛋白酶体和自噬体清除。p62在线粒体自噬等选择性自噬中发挥重要作用。p62与Keap1结合并通过自噬清除Keap1,这导致游离的Nrf2水平增加,而Nrf2又可促进p62表达。因此自噬、p62、Nrf2三者间存在密切的联系,相互调控。同时,Nrf2还可促进谷胱甘肽(Glutathione,GSH)和硫氧还蛋白(Thioredoxin,TXN)等多种分子的表达,而在肝缺血再灌注损伤过程中,肝细胞内这些分子可能参与细胞死亡的过程。因此,自噬与p62在肝缺血再灌注中的具体机制仍需进一步研究明确。     

人巨细胞病毒感染与细胞自噬的关系

人巨细胞病毒与宿主共同进化的漫长过程中,为促进自身的增殖和感染,HCMV也进化出多种策略利用或抵消自噬的影响。自噬是进化上高度保守的细胞降解途径,通过回收细胞质、细胞器和蛋白质以维持细胞内稳态。同时它也可以作为细胞防御机制,直接包裹降解病原体或通过促进先天性和适应性免疫以对抗多种病原体的侵袭。本文将对近年来有关HCMV与自噬关系的研究作一综述。     

线粒体自噬在脑缺血再灌注损伤中的研究进展

自噬(autophagy)是一种参与细胞器周转和蛋白质质量控制的细胞成分降解和再循环的调节机制.线粒体自噬(mitophagy)是线粒体质量控制的一种机制,功能失调的线粒体可以通过自噬选择性地被识别和移除.线粒体通过PINK1/Parkin、Bnip3、Bnip3L/Nix、FUNDC1和HUMMR等相关蛋白调控自噬,...     

饥饿诱导的细胞自噬可以引起UVRAG的降解

目的：观察细胞发生自噬后UVRAG水平的改变及其与自噬发生的关系。方法用Western印迹检测饥饿诱导细胞自噬后UVRAG分子的水平改变,然后分别应用自噬起始阶段与效应阶段的抑制剂抑制自噬,检测自噬不同阶段UVRAG分子的水平变化;结果饥饿促进了细胞LC3的型别转换和P62的降解,诱导细胞发生自噬;3-MA抑制细胞自噬及E64d和pepstatin抑制自噬溶酶体活性后,UVRAG的降解减少;结论饥饿诱导细胞自噬在形成自噬溶酶体后引起了UVRAG的降解。     

Autophagy,polyphenols and healthy ageing

Autophagy is a lysosomal degradation process that evolved as a starvation response in lower eukaryotes and has gained numerous functions in higher organisms. In animals, autophagy works as a central process in cellular quality control by removing waste or excess proteins and organelles. Impaired autophagy and the age-related decline of this pathway favour the pathogenesis of many diseases that occur especially at higher age such as neurodegenerative diseases and cancer. Caloric restriction (CR) promotes longevity and healthy ageing. Currently, the contributing role of autophagy in the context of CR-induced health benefits is being unravelled. Furthermore recent studies imply that the advantages from polyphenol consumption may be also connected to autophagy induction.In this review, the literature on autophagy regulation by (dietary) polyphenols such as resveratrol, catechin, quercetin, silibinin and curcumin is discussed with a focus on the underlying molecular mechanisms. Special attention is paid to the implications of age-related autophagy decline for diseases and the possibility of dietary countermeasures.     

Autophagy,its mechanisms and regulation: Implications in neurodegenerative diseases

Autophagy is a major regulatory cellular mechanism which gives the cell an ability to cope with some of the destructive events that normally occur within a metabolically living cell. This is done by maintaining the cellular homeostasis, clearance of damaged organelles and proteins and recycling necessary molecules like amino acids and fatty acids. There is a wide array of factors that influence autophagy in the state of health and disease. Disruption of these mechanisms may not only give rise to several autophagy-related disease, but also it can occur as the result of intracellular changes induced during disease pathogenesis causing exacerbation of the disease. Our knowledge is increasing regarding the role of autophagy and its mechanisms in the pathogenesis of various neurodegenerative diseases such as multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and Amyotrophic lateral sclerosis. Indeed, getting to know about the pathways of autophagy and its regulation can provide the basis for designing therapeutic interventions. In the present paper, we review the pathways of autophagy, its regulation and the possible autophagy-targeting interventions for the treatment of neurodegenerative disorders.     

细胞自噬与心血管疾病

细胞自噬是一种利用溶酶体对自身细胞器进行分解、将产生的大分子物质予以回收利用的高度保守的细胞降解过程。饥饿、缺血、氧化应激等均可诱导其发生。自噬在细胞的发育和分化过程中起着至关重要的作用,和许多心血管疾病的发生、发展密切相关。正常的细胞自噬对心肌细胞有保护作用,自噬不足或自噬过度则可促发疾病或加重病变。本文综述细胞自噬在心血管疾病中的研究进展。     

Selective degradation of p62 by autophagy

The autophagy–lysosome pathway is a highly conserved bulk degradation system in eukaryotes. During starvation, cytoplasmic constituents are non-selectively degraded by autophagy, and the resulting amino acids are utilized for cell survival. By taking advantage of mouse genetics, many physiological functions of mammalian autophagy have been uncovered. Growing lines of evidences have revealed the essential role of constitutive (or basal) autophagy in cellular homeostasis through its selectivity. p62, one of the selective substrates for autophagy, plays a key role in the formation of cytoplasmic proteinaceous inclusion, a hallmark of conformational diseases such as Alzheimer’s disease, Parkinson’s disease, and various chronic liver disorders. In this review, we discuss the physiological roles of the selective turnover of p62 by autophagy and their molecular mechanisms.     

Autophagy and lipids: tightening the knot

The degradation of intracellular components in lysosomes, also known as autophagy, participates in a broad range of cellular functions from cellular quality control to cellular remodeling or as mechanism of defense against cellular aggressors. In this review, we focus on the role of autophagy as an alternative source of cellular energy, particularly important when nutrients are scarce. Almost since the discovery of autophagy, it has been known that amino acids obtained through the breakdown of proteins in lysosomes are essential to maintaining the cellular energetic balance during starvation. However, it is only recently that the ability of autophagy to mobilize intracellular lipid stores as an additional source of energy has been described. Autophagy contributes thus to modulating the amount of cellular lipids and allows cells to adapt to lipogenic stimuli. Interestingly, this interplay between autophagy and lipid metabolism is bidirectional, as changes in the intracellular lipid content also contribute to modulating autophagic activity. In this review, we describe the recent findings on the contribution of autophagy to lipid metabolism in different tissues and the consequences that impairments in autophagy have on cellular physiology. In addition, we comment on the regulatory role that lipid molecules and their modifying enzymes play on different steps of the autophagic process.     

Autophagy as an immune defense mechanism

Autophagy is a homeostatic process whereby cytosol or intracellular organelles are sequestered by a double membrane structure termed autophagosome for subsequent delivery to lysosomes and degradation. Autophagy takes part in cell survival and death and has been implicated in development, aging, neurodegeneration and cancer. The newly discovered specialized role of autophagy in immune cells expands autophagic functions to defense against intracellular pathogens. Furthermore, autophagy is involved in acquired immunity, such as antigen processing for MHC II presentation, and is modulated by cytokines such as IFN-gamma. A further link has emerged between autophagy and defense against intracellular pathogens via the immunity-related GTPase lrgm1 (LRG-47), which has a protective role against Mycobacterium tuberculosis. We propose the term immunophagy for these defense processes.     

Autophagy in airway diseases: a new frontier in human asthma?

The study of autophagy (‘self‐eating’), a fundamental cell fate pathway involved in physiological and pathological subcellular processes, opens a new frontier in the continuous search for novel therapies for human asthma. Asthma is a complex syndrome with different disease phenotypes. Autophagy plays a central role in cell physiology, energy and metabolism, and cell survival. Autophagy's hallmark is the formation of double‐membrane autophagic autophagosomes, and this process is operational in airway epithelial and mesenchymal cells in asthma. Genetic associations between autophagy genes and asthma have been observed including single nucleotide polymorphisms in Atg5 which correlate with reduced lung function. Immune mechanisms important in asthma such as Th2 cells and eosinophils also manifest autophagy. Lastly, we address the role of autophagy in extracellular matrix deposition and fibrosis in asthmatic airways remodeling, a pathologic process still without effective therapy, and discuss potential pharmacologic inhibitors. We end by offering two opposing but plausible hypotheses as to how autophagy may be directly involved in airway fibrosis.     

Autophagy in tumor suppression and cancer therapy

Autophagy is a stress-induced cell survival program whereby cells under metabolic, proteotoxic, or other stress remove dysfunctional organelles and/or misfolded/polyubiquitylated proteins by shuttling them via specialized structures called autophagosomes to the lysosome for degradation. The end result is the release of free amino acids and metabolites for use in cell survival. For tumor cells, autophagy is a double-edged sword: autophagy genes are frequently mono-allelically deleted, silenced, or mutated in human tumors, resulting in an environment of increased oxidative stress that is conducive to DNA damage, genomic instability, and tumor progression. As such, autophagy is tumor suppressive. In contrast, it is important to note that although tumor cells have reduced levels of autophagy, they do not eliminate this pathway completely. Furthermore, the exposure of tumor cells to an environment of increased metabolic and other stresses renders them reliant on basal autophagy for survival. Therefore, autophagy inhibition is an active avenue for the identification of novel anti-cancer therapies. Not surprisingly, the field of autophagy and cancer has experienced an explosion of research in the past 10 years. This review covers the basic mechanisms of autophagy, discusses its role in tumor suppression and cancer therapy, and posits emerging questions for the future.     

Autofagia – proces o dwóch obliczach

Autophagy is a process that is involved in the pathogenesis of cancer but also in the development of resistance or sensitivity to cytostatic treatment applied.Until now, the issue is still unresolved if we should stimulate or inhibit the process of autophagy in cancer treatment through the use of appropriate anticancer therapy so that it is beneficial for the patient and induce remission of the disease. On the one hand autophagy as a mechanism of programmed cell death may also cause the death of tumor cells. On the other hand, as a defense mechanism is the process of cell survival strategy in stress situations such as hypoxia in the peripheral parts of the tumor or using cytostatic drugs.It would be good to find an answer if the autophagy is the process increasing the effectiveness of therapy or increasing resistance to treatment in a case of specific tumor.