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.     

细胞自噬在血管新生中作用的研究进展

自噬(autophagy)是细胞利用溶酶体降解自身受损的细胞器和大分子物质的过程,在稳定细胞内环境中发挥着重要作用。在血管新生的病理生理过程中,细胞自噬作用持续存在。从自噬的角度探索血管新生的发生发展进程,能够为临床治疗血管相关疾病提供新的思路。     

细胞自噬与动脉粥样硬化关系的研究进展

自噬是一种降解病原体和相关细胞器尤其是损伤的线粒体的分子机制,自噬也可清除其他的细胞成分,例如炎症和细胞因子,这为抗炎症提供了重要的途径.相关研究发现,自噬的产生或降解能够影响动脉粥样硬化斑块的发展过程.因此,在疾病出现时,自噬的调节对于疾病治疗的靶点具有重要的意义.然而,在正常情况和炎症反应时,自噬的调节方式是多方面的.这些错综复杂的改变是通过炎症和环境刺激所产生的,这对于了解和揭示自噬调节的炎症和提供相应的治疗方案是必不可少的.因而人了解自噬的分子机制,以及血管内皮细胞、血管平滑肌细胞、巨噬细胞自噬在动脉粥样硬化中起到的作用对于疾病的发展和靶向治疗具有重要意义.     

自噬在免疫及免疫相关疾病中的研究进展

自噬是细胞内溶酶体/内体参与的,涉及细胞增殖,分化及稳态平衡调节的降解过程.遗传学研究发现其在物种进化过程中较保守,从酵母到哺乳动物细胞中均有自噬相关基因的存在,提示自噬广泛参与各类生物正常的生理过程.近年来,随着研究的不断深入,人们发现自噬在许多疾病尤其在免疫相关疾病中亦扮演着重要角色,在感染,自身免疫,肿瘤免疫中所起的作用可为今后研究提供依据.     

自噬与心血管疾病

自噬是细胞在缺乏营养和能量供应时,部分胞质与细胞器被包裹并被降解为核苷酸、氨基酸及游离脂肪酸等小分子物质,再被重新利用合成大分子或者合成ATP的过程.自噬广泛参与多种疾病的发生,多种心血管疾病的病理过程伴随着心血管系统自噬活性的改变.     

线粒体自噬在器官纤维化疾病中作用的研究进展

线粒体自噬是一种选择性降解细胞中损伤或多余线粒体的特异性自噬现象,使细胞在应激损伤时能够维持线粒体数量和质量的稳定,从而维持细胞的正常表型和功能。其分子机制途径较为复杂,主要涉及PINK1/Parkin途径、NIX和BNIP3、FUNDC1等。线粒体自噬的异常与多种疾病密切相关,而调节不同阶段线粒体自噬分子机制在疾病发展中的作用已被重视。现就近年线粒体自噬在多种器官纤维化病变中的研究进展综述如下。     

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。     

自噬在自身炎症性疾病中的研究进展

自噬是真核生物对细胞应激物如错误折叠蛋白、长寿蛋白、受损的细胞器或胞内抗原进行降解的一种代谢途径。自噬与多种疾病相关,如神经退行性疾病、癌症等。现在发现,自噬与自身炎症性疾病(autoinflammatory disease, AUID)也存在较大关联。AUID是一类由遗传异质性因素引起的疾病,偶发性炎症、先天免疫反应失调等均会引起或加剧该类疾病的发生。已有研究表明,自噬通过对先天免疫信号传导途径的调控,可以对炎症水平进行控制。AUID相关的遗传变体可以直接激活炎症信号通路,而这些变体也可能造成自噬功能损伤,从而间接增加炎症反应水平。AUID中的遗传变体可以通过不同的机制对自噬造成损伤,文章就几种AUID中相关变体对自噬影响的反应途径及作用机制进行综述,以期为自噬作为治疗AUID的靶点提供新的策略。     

ROS介导的自噬及其在相关疾病中的作用

传统观念认为,活性氧类(reactive oxygen species,ROS)只是一类损伤细胞的毒性物质,近年的研究发现ROS作为一种信号分子参与细胞的增殖、分化及凋亡等多个生理过程.自噬是一种溶酶体依赖性的细胞内大分子物质和细胞器的降解过程,不仅在生理情况下发挥重要作用且参与一些疾病的发生发展[1-3].最新的研究表明ROS,特别是线粒体源性ROS,作为信号分子参与自噬的调节.本文集中讨论了ROS和自噬的关系以及ROS介导的自噬在疾病发生发展中的作用,从而为疾病的治疗提供新的靶点和策略.     

基于自噬相关基因的肝细胞癌患者预后预测模型的构建EI北大核心CSCD

自噬是一种程序性细胞降解过程,与包括恶性肿瘤在内的多种生理和病理过程有关。自噬的异常诱导在肝细胞癌的发展中起着关键作用,因此我们基于自噬相关基因进行了肝细胞癌患者预后预测模型的构建。从癌症基因组图谱数据库中检索到204个差异表达的自噬相关基因以及377例已登记的肝细胞癌患者的基本信息和临床特征。采用Cox风险回归分析确定与生存相关的自噬相关基因,并在此基础上构建预后相关预测模型。在肝细胞癌患者中总共鉴定出64个差异表达的自噬相关基因。经单因素和多因素Cox回归分析后确定5个与肝细胞癌患者预后相关的危险因子,包括TMEM74、BIRC5、SQSTM1、CAPN10和HSPB8。将年龄、性别、肿瘤分级和分期以及风险评分作为变量纳入多因素Cox回归分析,结果显示风险评分是肝细胞癌患者的独立预后危险因素(HR=1.475,95%CI=1.280~1.699,P<0.001)。此外,预后风险模型的曲线下面积为0.739,表明该模型在预测肝细胞癌预后方面具有较高准确性。结果表明我们将肝细胞癌患者的分子特征和临床参数相结合所建立的新的预后风险模型,可以有效地预测肝癌患者预后。     

Expression of Ambra1 in mouse brain during physiological and Alzheimer type aging

Autophagy is a major protein degradation pathway, essential for stress-induced and constitutive protein turnover. In nervous tissue, autophagy is constitutively active and crucial to neuronal survival. The efficiency of the autophagic pathway reportedly undergoes age-related decline, and autophagy defects are observed in neurodegenerative diseases. Since Ambra1 plays a fundamental role in regulating the autophagic process in developing nervous tissue, we investigated the expression of this protein in mature mouse brain and during physiological and Alzheimer type aging. The present study accomplished the first complete map of Ambra1 protein distribution in the various brain areas, and highlights differential expression in neuronal/glial cell populations. Differences in Ambra1 content are possibly related to specific neuronal features and properties, particularly concerning susceptibility to neurodegeneration. Furthermore, the analysis of Ambra1 expression in physiological and pathological brain aging supports important, though conflicting, functions of autophagy in neurodegenerative processes. Thus, novel therapeutic approaches, based on autophagy modulation, should also take into account the age-dependent roles of this mechanism in establishing, promoting, or counteracting neurodegeneration.     

Autophagic machinery activated by dengue virus enhances virus replication

Autophagy is a cellular response against stresses which include the infection of viruses and bacteria. We unravel that Dengue virus-2 (DV2) can trigger autophagic process in various infected cell lines demonstrated by GFP-LC3 dot formation and increased LC3-II formation. Autophagosome formation was also observed under the transmission electron microscope. DV2-induced autophagy further enhances the titers of extracellular and intracellular viruses indicating that autophagy can promote viral replication in the infected cells. Moreover, our data show that ATG5 protein is required to execute DV2-induced autophagy. All together, we are the first to demonstrate that DV can activate autophagic machinery that is favorable for viral replication.     

Autophagy dysregulation in amyotrophic lateral sclerosis

Autophagy is an intracellular lysosomal degradation process, which plays an important role in cell growth and development, and keeping cellular homeostasis in all eukaryotes. Autophagy has multiple physiological functions, including protein degradation, organelle turnover and response to stress. Emerging evidences support the notion that dysregulation of autophagy might be critical for pathogenesis of amyotrophic lateral sclerosis (ALS). The autophagy dysregulation in motor neurons of ALS may occur in different steps of the autophagic process. Recent studies have shown that two ALS associated proteins, TDP-43 and superoxide dismutase 1 (SOD1), are involved in the abnormal autophagy regulation. Furthermore, it is reported that several genetic mutations in ALS disturb the autophagic process in the motor neurons. This review will provide new evidence of autophagy dysregulation as a critical pathogenic process leading to ALS, and will discuss the prospect of future therapeutic targets using autophagic regulation to treat this disease.     

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.     

Roles of bovine viral diarrhea virus envelope glycoproteins in inducing autophagy in MDBK cells

Macroautophagy (autophagy) is an evolutionarily conserved control process that maintains cellular homeostasis in eukaryotic cells. Autophagy principally serves an adaptive role to degrade dysfunctional proteins and to clean damaged organelles in response to pathogenic, viral, or microbial infection, nutrient deprivation and endoplasmic reticulum (ER) stress. In previous study, we showed bovine viral diarrhea virus (BVDV) NADL infection induced autophagy and significantly elevated the expression levels of autophagy-related genes, Beclin1 and ATG14, at 12 h post-infection in MDBK cells. However, the specific mechanisms involved in controlling autophagic activity remain unclear. Here, we investigate the effects of BVDV NADL envelope glycoproteins overexpression on inducing autophagy. The results show that viral envelope glycoproteins E^rns and E2 overexpression mediated by lentivirus increase the formation of autophagosome, the percentage of GFP-LC3 puncta-positive cells and the expression levels of Beclin1 and ATG14. Whereas E1 overexpression doesn't affect autophagic activity. Collectively, these findings suggest that the viral envelope glycoproteins E^rns and E2 are involved in inducing autophagy, and provide a mechanistic insight into the regulation of autophagy in viral infected cells.     

Autophagy and disease: always two sides to a problem

Autophagy is a process traditionally known to contribute to cellular cleaning through the removal of intracellular components in lysosomes. In recent years, intensive scrutiny at the molecular level to which autophagy has been subjected has also contributed to expanding our understanding of the physiological role of this pathway. Added to the well-characterized role in quality control, autophagy has proved to be important in the maintenance of cellular homeostasis and of the energetic balance, in cellular and tissue remodelling, and cellular defence against extracellular insults and pathogens. It is not a surprise that, in light of this growing number of physiological functions, connections between autophagic malfunction and human pathologies have also been strengthened. In this review, we focus on several pathological conditions associated with primary or secondary defects in autophagy and comment on a recurring theme for many of them, ie the fact that autophagy can often exert both beneficial and aggravating effects on the progression of disease. Elucidating the factors that determine the switch between these dual functions of autophagy in disease has become a priority when considering the potential therapeutic implications of the pharmacological modulation of autophagy in many of these pathological conditions.     

Dual roles of autophagy in the survival of Caenorhabditis elegans during starvation

Autophagy is a major pathway used to degrade long-lived proteins and organelles. Autophagy is thought to promote both cell and organism survival by providing fundamental building blocks to maintain energy homeostasis during starvation. Under different conditions, however, autophagy may instead act to promote cell death through an autophagic cell death pathway distinct from apoptosis. Although several recent papers suggest that autophagy plays a role in cell death, it is not known whether autophagy can cause the death of an organism. Furthermore, why autophagy acts in some instances to promote survival but in others to promote death is poorly understood. Here we show that physiological levels of autophagy act to promote survival in Caenorhabditis elegans during starvation, whereas insufficient or excessive levels of autophagy contribute to death. We found that inhibition of autophagy decreases survival of wild-type worms during starvation, and that muscarinic signaling regulates starvation-induced autophagy, at least in part, through the death-associated protein kinase signaling pathway. Furthermore, we found that in gpb-2 mutants, in which muscarinic signaling cannot be down-regulated, starvation induces excessive autophagy in pharyngeal muscles, which in turn, causes damage that may contribute to death. Taken together, our results demonstrate that autophagy can have either prosurvival or prodeath functions in an organism, depending on its level of activation.     

Morphological and biochemical studies on aging and autophagy

To maintain health in the elderly is a crucial objective for modern medicine that involves both basic and clinical researches. Autophagy is a fundamental auto-cannibalizing process that preserves cellular homeostasis and, if altered, either by excess or defect, greatly changes cell fate and can result in incapacitating human diseases. Efficient autophagy may prolong lifespan, but unfortunately this process becomes less efficient with age.The present review is focused on the close relationship between autophagy and age-related disorders in different tissues/organs and in transgenic animal models. In particular, it comments on the up to date literature on mechanisms responsible for age-related impairment of autophagy. Moreover, before discussing about these mechanisms, it is necessary to describe the metabolic autophagic regulation of autophagy and the proteins involved in this process. At the end, these data would summarize the autophagic link with aging process, as important tools in the future biogerontology scenario.     

TBK-1 Promotes Autophagy-Mediated Antimicrobial Defense by Controlling Autophagosome Maturation

Autophagy is a fundamental biological process of the eukaryotic cell contributing to diverse cellular and physiological functions including cell-autonomous defense against intracellular pathogens. Here, we screened the Rab family of membrane trafficking regulators for effects on autophagic elimination of Mycobacterium tuberculosis var. bovis BCG and found that Rab8b and its downstream interacting partner, innate immunity regulator TBK-1, are required for autophagic elimination of mycobacteria in macrophages. TBK-1 was necessary for autophagic maturation. TBK-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on Ser-403, a residue essential for its role in autophagic clearance. A key proinflammatory cytokine, IL-1β, induced autophagy leading to autophagic killing of mycobacteria in macrophages, and this IL-1β activity was dependent on TBK-1. Thus, TBK-1 is?a key regulator of immunological autophagy and is responsible for the maturation of autophagosomes into lytic bactericidal organelles.