Autophagy in coxsackievirus-infected neurons

Autophagy is a process to engulf aberrant organelles or protein aggregates into double-membrane vesicles for lysosomal breakdown. Autophagy is a protective process against some intracellular bacteria and viruses, however, it is also used for replication by some viruses, such as poliovirus. We recently found that coxsackievirus B4 (CVB4) also induces the autophagy pathway and activates the calpain system for replication in neurons. Notably, the inhibition of autophagy with 3-methyladenine (3MA) reduced calpain activation and virus replication. Calpain inhibitors also reduced autophagosome formation and virus replication. This finding indicates that calpain and the autophagy pathway are closely connected with each other during the infection. Interestingly, we also found that 3MA and calpain inhibitors enhanced the caspase-3 specific cleavage of spectrin during CVB4 infection, suggesting that autophagy inhibition by these drugs triggered apoptosis. Thus, autophagy and apoptosis may balance each other in CVB4-infected neurons. Here, we show that inhibition of caspase with zVAD increased autophagosome formation, further proposing the cross-talk between autophagy and apoptosis in CVB4-infected neurons.     

肿瘤细胞的自噬和窖蛋白-1

自噬作用是一种细胞通过溶酶体自我降解的过程,在肿瘤的形成和发展中起着双重作用。窖蛋白-1(Caveolin-1,Cav-1)作为胞膜窖的标志蛋白,介导许多生理和病理过程,包括胞膜窖的形成、膜泡运输、维持细胞胆固醇稳态、信号转导和肿瘤的发生。近年来,许多研究表明肿瘤细胞自噬和Cav-1存在一定关系。文中就近年来肿瘤细胞的自噬与Cav-1的关系及其在肿瘤发生和发展过程中的作用进行综述。     

Autophagy in yeast: a review of the molecular machinery

Autophagy is a membrane trafficking mechanism that delivers cytoplasmic cargo to the vacuole/lysosome for degradation and recycling. In addition to non-specific bulk cytosol, selective cargoes, such as peroxisomes, are sorted for autophagic transport under specific physiological conditions. In a nutrient-rich growth environment, many of the autophagic components are recruited for executing a biosynthetic trafficking process, the cytoplasm to vacuole targeting (Cvt) pathway, that transports the resident hydrolases aminopeptidase I and alpha-mannosidase to the vacuole in Saccharomyces cerevisiae. Recent studies have identified pathway-specific components that are necessary to divert a protein kinase and a lipid kinase complex to regulate the conversion between the Cvt pathway and autophagy. Downstream of these proteins, the general machinery for transport vesicle formation involves two novel conjugation systems and a putative membrane protein complex. Completed vesicles are targeted to, and fuse with, the vacuole under the control of machinery shared with other vacuolar trafficking pathways. Inside the vacuole, a potential lipase and several proteases are responsible for the final steps of vesicle breakdown, precursor enzyme processing and substrate turnover. In this review, we discuss the most recent developments in yeast autophagy and point out the challenges we face in the future.     

猪丁型冠状病毒感染引致细胞自噬的研究进展

细胞自噬是利用溶酶体对细胞内多余、受损、死亡的蛋白质和细胞器进行降解的一种过程。细胞受到病毒等刺激时,为了维持内环境稳态,细胞自噬常有发生,虽然细胞自噬可以有效抵抗病毒入侵,但这个过程也会对病毒感染产生负作用。猪丁型冠状病毒(porcine deltacoronavirus,PDCoV)感染细胞时会引发细胞发生自噬现象。本文从自噬的种类和发生流程、自噬与PDCoV互作及相关检测方法等方面,对细胞自噬在PDCoV感染中如何抵抗和促进病毒复制进行了阐述,对进一步研究PDCoV致病机制和防控具有积极意义。     

Autophagy in neurons: it is not all about food

The primary function of autophagy in most cell types is adaptation to starvation. Because neurons are protected from this type of stress, the physiological role of autophagy in normal functioning neurons was, until now, poorly understood. Using genetic manipulations to block autophagy in neurons selectively, Mizushima's and Tanaka's groups have recently presented conclusive evidence for an essential role of constitutive autophagy in neuronal survival. These studies provide new insights into the relationship between autophagy malfunctioning and neurodegenerative disorders.     

Autophagy and inflammation: A special review issue

Macroautophagy/autophagy is a fundamental intracellular homeostatic process that is of interest both for its basic biology and for its effect on human physiology in a wide spectrum of conditions and diseases. Autophagy was first appreciated primarily as a metabolic and cytoplasmic quality control process, but in the past decade its role in immunity has been steadily growing. The connections between these aspects beckon explorations of the network and connections that exist between metabolism, quality control, and inflammation and immunity processes, which are so key to many human diseases including neurodegeneration, obesity and diabetes, chronic inflammatory conditions, cancer, infection, and aging. The purpose of this issue is to stimulate further the burgeoning studies of the intersections between autophagy and inflammation, and the inevitable overlaps with metabolic and quality control functions of autophagy.     

Autophagy: a sweet process in diabetes

Autophagy is inhibited by the insulin-amino acid-mTOR signaling pathway. Two papers in this issue of Cell Metabolism (Ebato et al., 2008; Jung et al., 2008) provide evidence that basal autophagy is necessary to maintain the architecture and function of pancreatic beta cells and that its induction in diabetic mice protects beta cells against damage by oxidative stress.     

Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance

Macroautophagy is a lysosomal degradative pathway that maintains cellular homeostasis by turning over cellular components. Here we demonstrate a role for autophagy in hypothalamic agouti-related peptide (AgRP) neurons in the regulation of food intake and energy balance. We show that starvation-induced hypothalamic autophagy mobilizes neuron-intrinsic lipids to generate endogenous free fatty acids, which in turn regulate AgRP levels. The functional consequences of inhibiting autophagy are the failure to upregulate AgRP in response to starvation, and constitutive increases in hypothalamic levels of pro-opiomelanocortin and its cleavage product α-melanocyte-stimulating hormone that typically contribute to a lean phenotype. We propose a conceptual framework for considering how autophagy-regulated lipid metabolism within hypothalamic neurons may modulate neuropeptide levels to have immediate effects on food intake, as well as long-term effects on energy homeostasis. Regulation of hypothalamic autophagy could become an effective intervention in conditions such as obesity and the metabolic syndrome.     

Autophagy: a pathogen driven process

Host cell recognition and eradication of invading pathogens is crucial for the control of microbial infections. However, several microorganisms develop tactics that allow them to survive intracellularly. Autophagy, a process involved in protein turnover and in charge of the removal of aged organelles by degradation of engulfed cytoplasmic portions, was recently shown to play a clear role in the detection and elimination of intracellular pathogens. Yet, some pathogens employ elegant strategies to elude entrapment in autophagosomes, and thus to avoid lysosomal degradation, whereas others utilize the autophagy pathway for their own benefit. In this review some recent findings on the relationship between microorganisms and autophagy are summarized, the underlying assumption being that intracellular infection models may contribute to the understanding of the molecular mechanisms involved in the autophagic process.     

Autophagy: a target for retinoic acids

Autophagy is an intracellular catabolic process that responds with great sensitivity to nutrient availability, implying that certain macro- or micro-nutrients are involved. We found that retinoic acid promotes autophagosome maturation through a pathway independent from the classic nuclear retinoid receptors. Retinoic acid redistributes the cation-independent mannose-6-phosphate receptor from the trans-Golgi region to maturing autophagosomal structures inducing their acidification. Manipulation of the autophagic activity by retinoids could have enormous health implications, since they are essential dietary components and frequently used pharmaceuticals.     

Autophagy by ARF: a short story

In this issue of Molecular Cell, Reef et al. (2006) describe a shortened unstable form of the ARF tumor suppressor protein that localizes within mitochondria, where it reduces membrane potential and triggers autophagy. Could this account for the Mdm2- and p53-independent tumor suppressive effects of ARF?     

Autophagy: a Novel Protective Mechanism in Chronic Ischemia

During the search for cardioprotective mechanisms in a porcine model of chronic myocardial ischemia and hibernating myocardium, we discovered evidence for autophagy, which could be involved in the protection against apoptosis. Autophagy is a cellular degradation process responsible for the turnover of unnecessary or dysfunctional organelles and cytoplasmic proteins, which become sequestered in a double-membrane-bound vesicle, termed autophagosome, and subsequently degrade upon fusion with lysosomes. The dauer phase in C. elegans shares similarities with the induction of autophagy in chronically ischemic (hibernating) myocardium. In this sense, autophagy is an essential mechanism for survival which is activated by environmental stresses and confers stress resistance to the organism. Our study provided insight into understanding of the protective mechanism of autophagy in chronic ischemia.     

Metabolic signaling between neurons and glial cells: a short review.

There is convincing evidence that astrocytes transform blood-born glucose to lactate, alpha-Keto-glutarate and alanine and supply the neurons. There is a tight regulation of this metabolic coupling by means of chemical signals released by functioning neurons. Previous, pioneer, studies have explored several signals-candidates the major being K(+), Ca(++) and several neuromodulators. However, recent results of numerous studies identify glutamate as the major signal that traffics between excited neurons and astrocytes. The excited neurons also produce and release NH(4)(+) in the extracellular space. Both glutamate and ammonium are taken up preferentially by astrocytes and form glutamine. Ammonia fixation by glutamine synthase controls the amount of lactate, glutamine and alanine produced and released by Muller cells in the extracellular space and then taken up by neurons. Thus, there is a tight coupling between function and metabolism in the central neurons system.     

Autophagy in neuronal cell loss: a road to death

The regulation of ageing has been extensively studied in divergent animal model systems including worms, flies and mice. However, little is known about the cellular pathways that mediate the death of these organisms. Analysing major cellular changes in the ageing nematode Caenorhabditis elegans has revealed a gradual, progressive deterioration of different tissues except for the nervous system, which remarkably preserves its integrity even in advanced old age. In addition, genetic data have shown that, in C. elegans and in the fruit fly Drosophila melanogaster, lifespan is controlled by signals derived from neurons and acting throughout adulthood. Organismal death thus seems to be a consequence of the decline of specific neurons. Accumulating evidence demonstrates that late onset of neuronal cell loss generally occurs via autophagy, a process in which eukaryotic cells self-digest parts of their contents during development or to survive starvation. Here we suggest that overactivation of autophagy in the cells of the nervous system is the eventual cause of "physiological" death.     

Autophagy: a new player in hepatic stellate cell activation

Hepatic stellate cell (HSC) activation, the transition from a resident quiescent HSC to a myofibroblastic collagen-producing HSC, is a fundamental feature of liver fibrosis. Autophagy has been implicated in major liver pathologies, such as HCV infection and hepatocarcinoma. However, its role in HSC biology is largely unknown. Recently, we were able to demonstrate that HSC activation is followed by an increased autophagic flux and that its inhibition can partially inhibit the HSC myofibroblastic transition. These results point to autophagy as a possible target in the prevention of HSC activation.