神经干细胞自噬与自噬机制研究现状

<正>自噬(autophagy)作为细胞内物质代谢的重要方式,是亚细胞膜内的结构发生动态变化,也是溶酶体介导细胞内蛋白质和细胞器降解的正常新陈代谢过程。细胞死亡包括坏死、凋亡和自噬三种形式。在细胞平衡合成和分解代谢过程中,通过自噬保持细胞内环境的稳定,使细胞自我更新,保持活力[1-4]。自噬不足则细胞衰老,过度则出现程序性细胞死亡     

自噬/苄氯素1调节因子1在自噬与凋亡中作用的研究进展

细胞凋亡(Ⅰ型程序性死亡)和自噬性细胞死亡(Ⅱ型程序性死亡)这2种细胞死亡方式可通过一些蛋白的相互作用而介导形成平衡对立状态.一方面,细胞凋亡由胱天蛋白酶(caspase,CASP)依赖性通路经内源性、外源性或内质网应激诱导途径予以控制,而死亡信号则可经这3种途径介导受损或感染细胞的清除[1-2].另一方面,细胞自噬由...     

泛素与自噬

泛素调节的蛋白质降解过程和细胞的自噬现象都是细胞自我调节的基本机制.其中,泛素可能作为一种普遍的识别信号参与了自噬过程;而自噬的诱导又能促进泛素化作用,从而增强对底物的降解.本文着重探讨这两者间的关系及可能存在的相互调节作用,并兼及两者共同涉及的细胞程序性死亡现象.     

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.     

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。     

自噬相关基因Beclin 1与肿瘤

自噬性细胞死亡是一种不同于凋亡、不依赖于caspase的程序性细胞死亡。研究发现自噬活性的变化、自噬性细胞死亡与恶性肿瘤的发生、发展有关。某些癌基因、抑癌基因参与了自噬活性的调节，其中对Beclin1研究较多，它作为自噬相关基因参与调节自噬活性，从而在肿瘤的发生、发展中发挥作用。现对Beclin1、自噬与肿瘤发生、发展关系的最新进展作一综述。     

细胞自噬在急性肺损伤发展进程中的双刃剑作用

急性肺损伤(acute lung injury,ALI)是急危重症患者常见的一种器官损伤,肺实质细胞死亡是ALI的基础,明确细胞死亡的发生机制将为防治ALI提供重要的理论支撑[1]。细胞自噬(autophagy)是细胞代谢过程中的衰老细胞器和异常蛋白质等成分降解的过程,受多条信号通路与多种信号分子的调节,有利于维持细胞稳态;病理状态下.     

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。     

自噬基因Beclin 1 shRNA表达质粒的构建及其下调凋亡因子caspase-9效应的研究

构建自噬基因Beclin 1的小发夹RNA(shRNA)真核表达质粒,脂质体包裹后体外转染人宫颈癌HeLa细胞株,通过荧光定量PCR(RT-PCR)和Western blot检测其对HeLa细胞自噬基因Beclin 1 mRNA及蛋白表达的影响,并检测细胞增殖、细胞周期、细胞凋亡情况以及凋亡因子caspase-9 mRNA及蛋白表达的变化。结果表明shRNA真核表达载体可以使HeLa细胞中自噬基因Beclin 1的mRNA及其蛋白含量降低,转染后细胞生长增殖速度加快,凋亡率降低,并伴有caspase-9 mRNA及蛋白量的显著下调。因此,Beclin 1不仅与自噬调控通路有关,而且可以调控凋亡的发生,同时参与两种程序性细胞死亡的过程。     

缺血缺氧状态下细胞自噬的研究进展

自噬是广泛存在于真核细胞内的一种细胞分解细胞质等自身构成成分的生理现象.自噬在各种生命活动中发挥着重要作用,例如它可以加速细胞内的新陈代谢,或者在细胞处于缺血缺氧等饥饿状态时从分解产物中获得能量.大量研究表明增强的自噬促进了细胞在缺血缺氧等饥饿状态下的存活.然而,如果自噬水平过度上调,将引起自噬性细胞死亡,也称为Ⅱ型程序性细胞死亡.     

Autophagy plays a protective role as an anti‐oxidant system in human T cells and represents a novel strategy for induction of T‐cell apoptosis

Autophagy is an intracellular degradation system that plays an important role in T‐cell survival. However, the precise mechanism linking autophagy and cell death in primary human T cells is unclear because methods for monitoring autophagy in small numbers of primary human cells remain controversial. We established a novel method for assessing autophagy in activated human T cells using a retroviral GFP–LC3 expression system. We found that autophagy was induced after TCR stimulation and that autophagy‐defective naïve CD4⁺ T cells were susceptible to apoptosis through the intrinsic apoptotic pathway. Enhanced apoptosis of autophagy‐defective T cells resulted from accumulation of ROS due to impaired mitophagy. We also demonstrated that effector memory CD4⁺ T cells had lower autophagic activity than naïve CD4⁺ T cells, which contributed to their enhanced apoptosis due to increased ROS. Moreover, blocking autophagy increased intracellular mitochondrial volume and ROS levels in activated T cells. These results suggest a protective role of autophagy as an anti‐oxidant system in activated human T cells. The combination of an autophagy blocker and a mitochondrial electron transport chain inhibitor has a synergistic effect on T‐cell death, which could be a novel strategy for induction of T‐cell apoptosis.     

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。     

自噬与软骨细胞生存及软骨损伤

背景：自噬是细胞通过溶酶体途径处理内源性底物的过程,它普遍存在于机体细胞中,又被看作是细胞Ⅱ型程序性死亡,自噬可能是正常软骨细胞的一种保护或平衡机制。 目的：就自噬与软骨及其损伤相关性的最新研究进展进行讨论,旨在对自噬在软骨及其损伤修复中的作用有一个更好的理解。 方法：应用计算机检索中国知网、万方数据库及PubMed数据库最近20年有关自噬与软骨损伤方面的文献,中文检索词为“自噬、软骨、软骨细胞”,英文检索词为“autophagy、cartilage、chondrocytes、beclin1、LC3”。 结果与结论：软骨细胞能感受关节内微环境变化而做出应答,以调整细胞基质代谢,维持关节软骨生物学功能,而软骨细胞所处低氧环境是引起细胞自噬的重要因素。自噬是正常软骨细胞的一种平衡或者保护机制,虽然自噬与软骨及其损伤相关性在近些年的研究中取得了长足的进步,但不得不承认其仍处于初级阶段,在分子水平上一些Atg的发现加深了对自噬的认识,但在软骨中如何诱导自噬途径,自噬信号是如何传导的,对软骨细胞生存会产生怎样的影响等方面的了解还不够丰富,有待广大学者进一步研究。     

AMPK-mTOR-ULK1/2信号通路与自噬

自噬(autophagy)又称Ⅱ型细胞死亡,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.研究发现,自噬与多种疾病的发生发展密切相关,包括阿尔兹海默症、心肌病、肿瘤.AMPK-mTOR-ULK1/2信号通路对自噬具有重要的调控作用,对该通路的深入研究将有助于更好地理解细胞自噬过程,并为自噬相关疾病的治疗提供新的靶点.该文总结了AMPK-mTOR-ULK1/2信号通路中各分子的作用及其对自噬的调控机制及相关研究进展.     

Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability

Two major protein degradation systems exist in cells, the ubiquitin proteasome system and the autophagy machinery. Here, we investigated the functional relationship of the two systems and the underlying mechanisms. Proteasome inhibition activated autophagy, suggesting that the two are functionally coupled. Autophagy played a compensatory role as suppression of autophagy promoted the accumulation of polyubiquitinated protein aggregates. Autophagy was likely activated in response to endoplasmic reticulum stress caused by misfolded proteins during proteasome inhibition. Suppression of a major unfolded protein response pathway mediated by IRE1 by either gene deletion or RNA interference dramatically suppressed the activation of autophagy by proteasome inhibitors. Interestingly, c-Jun NH(2)-terminal kinase (JNK) but not XBP-1, both of which are the known downstream targets of IRE1, seemed to participate in autophagy induction by proteasome inhibitors. Finally, proteasome inhibitor-induced autophagy was important for controlling endoplasmic reticulum stress and reducing cell death in cancer cells. Our studies thus provide a mechanistic view and elucidate the functional significance of the link between the two protein degradation systems.     

Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis

Autophagy is a catabolic process involving self-digestion of cellular organelles during starvation as a means of cell survival; however, if it proceeds to completion, autophagy can lead to cell death. Autophagy is also a haploinsufficient tumor suppressor mechanism for mammary tumorigenesis, as the essential autophagy regulator beclin1 is monoallelically deleted in breast carcinomas. However, the mechanism by which autophagy suppresses breast cancer remains elusive. Here we show that allelic loss of beclin1 and defective autophagy sensitized mammary epithelial cells to metabolic stress and accelerated lumen formation in mammary acini. Autophagy defects also activated the DNA damage response in vitro and in mammary tumors in vivo, promoted gene amplification, and synergized with defective apoptosis to promote mammary tumorigenesis. Therefore, we propose that autophagy limits metabolic stress to protect the genome, and that defective autophagy increases DNA damage and genomic instability that ultimately facilitate breast cancer progression.     

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.     

Viral interactions with macroautophagy: A double-edged sword

Autophagy is a conserved eukaryotic mechanism that mediates the removal of long-lived cytoplasmic macromolecules and damaged organelles via a lysosomal degradative pathway. Recently, a multitude of studies have reported that viral infections may have complex interconnections with the autophagic process. These observations strongly imply that autophagy has virus-specific roles relating to viral replication, host innate and adaptive immune responses, virus-induced cell death programs, and viral pathogenesis. Autophagy can supply internal membrane structures necessary for viral replication or may prolong cell survival during viral infections and postpone cell death. It can influence the survival of both infected and bystander cells. This process has also been linked to the recognition of viral signature molecules during innate immunity and has been suggested to help rid the cell of infection. This review discusses interactions between different viruses and the autophagy pathway, and surveys the current state of knowledge and emerging themes within this field.     

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.     

Innate and adaptive immunity through autophagy

The two main proteolytic machineries of eukaryotic cells, lysosomes and proteasomes, receive substrates by different routes. Polyubiquitination targets proteins for proteasomal degradation, whereas autophagy delivers intracellular material for lysosomal hydrolysis. The importance of autophagy for cell survival has long been appreciated, but more recently, its essential role in both innate and adaptive immunity has been characterized. Autophagy is now recognized to restrict viral infections and replication of intracellular bacteria and parasites. Additionally, this pathway delivers cytoplasmic antigens for MHC class II presentation to the adaptive immune system, which then in turn is able to regulate autophagy. At the same time, autophagy plays a role in the survival and the cell death of T cells. Thus, the immune system utilizes autophagic degradation of cytoplasmic material, to both restrict intracellular pathogens and regulate adaptive immunity.