Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Autophagy”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 253 records · Page 14Linked to original sources
PubMed2006

Induction of autophagy in axonal dystrophy and degeneration.

Autophagy is a highly regulated cellular mechanism for the bulk degradation of cytoplasmic contents. It has been implicated in a variety of physiological and pathological conditions relevant to neurological diseases. However, the regulation of autophagy in neurons and its role in neuronal and axonal pathology are not yet understood. Using transgenic mice producing green fluorescent protein-tagged autophagic marker microtubule-associated protein light chain 3 (GFP-LC3), we provide molecular evidence for the induction of autophagy in axonal dystrophy and degeneration in Purkinje cells of the Lurcher mice, a model for excitotoxic neurodegeneration. We show that the excitotoxic insult of Lurcher mutation triggers an early response of Purkinje cells involving accumulation of GFP-LC3-labeled autophagosomes in axonal dystrophic swellings (a hallmark of CNS axonopathy). In brain, LC3 interacts with high affinity with the microtubule-associated protein 1B (MAP1B). We show that MAP1B binds to LC3 of both cytosolic form (LC3I) and lipidated form (LC3II). Moreover, in cell culture, overexpression of MAP1B results in reduced LC3II levels and number of GFP-LC3-labeled autophagosomes; phosphorylated MAP1B is associated with GFP-LC3-labeled autophagosomes. Furthermore, in brain, phosphorylated MAP1B accumulates in axonal dystrophic swellings of degenerating Purkinje cells and binds to LC3 at increased level. Therefore, the MAP1B-LC3 interaction may participate in regulation of LC3-associated autophagosomes in neurons, in particular at axons, under normal and pathogenic conditions. We propose that induction of autophagy serves as an early stress response in axonal dystrophy and may participate in the remodeling of axon structures.

Animals↗
PubMed2005

Dyneins, autophagy, aggregation and neurodegeneration.

We recently showed that the dynein motor machinery plays a role in the delivery of autophagosome contents to lysosomes, in the process of autophagosome-lysosome fusion. This may explain a number of important previous observations, including why intracellular aggregates form in mice with dynein mutations that have motor neuron-like disease. These studies highlight the importance of dyneins and autophagy in the clearance of aggregate-prone proteins in general, and also in the specific case of Huntington's disease. Since many common neurodegenerative diseases are associated with intracellular aggregate formation but the causative variants are unknown, it may be worth considering the possibility of genetic lesions affecting autophagy as contributing factors in such disorders. The importance of dyneins in autophagosome-lysosome fusion provides new insights for the microtubule dependency of autophagy. In this Addendum, we review our findings in the contexts of autophagy and neurodegeneration and consider some of the questions raised.

Animals↗
PubMed2006

Autophagy and related processes in trypanosomatids: insights from genomic and bioinformatic analyses.

The targeting in eukaryotic cells of cellular components to the lysosome or vacuole for degradation is called autophagy. Not only cytoplasmic macromolecules and bulk cytoplasm are subject to this process; entire organelles such as peroxisomes can be degraded. Autophagy of peroxisomes is called pexophagy. Unpublished evidence suggests that the analogous processing of glycosomes in the protozoan kinetoplastids occurs. Taking advantage of the (near-) complete status of three trypanosomatid genomes, a census of components of autophagy and related processes has been undertaken in these organisms. Simple database searches were supplemented by more advanced analyses where necessary. At most, only half of the components characterized in yeasts are present in trypanosomatids suggesting an unexpectedly streamlined version of autophagy occurs in these organisms. The cytoplasm-to-vacuole targeting (Cvt) system for delivery of proteins to the vacuole seems entirely absent in trypanosomatids. The accuracy of the census is supported by the coordinated absence of functionally linked components such as the conjugation system involving ATG12, ATG5, ATG10 and ATG16 that acts at the step of vesicle expansion and completion. Overall, the results are consistent with a scenario of taxon-specific addition of components to a minimal core, a hypothesis that should be readily testable by further genomic surveys allied to laboratory experiments. A bioinformatics analysis of the trypanosomatidal proteins was carried out, highlighting the paucity of information available regarding their structures and enabling prioritization of targets for future structural biology work.

Animals↗
PubMed2006

p62/SQSTM1: a missing link between protein aggregates and the autophagy machinery.

In eukaryotic cells short-lived proteins are degraded in a specific process by the ubiquitin-proteasome system (UPS), whereas long-lived proteins and damaged organelles are degraded by macroautophagy (hereafter referred to as autophagy). A growing body of evidence now suggests that autophagy is important for clearance of protein aggregates that form in cells as a consequence of ageing, oxidative stress, alterations that elevate the amounts of certain aggregation-prone proteins or expression of aggregating mutant variants of specific proteins. Autophagy is generally considered to be a non-specific, bulk degradation process. However, a recent study suggests that p62/SQSTM1 may link the recognition of polyubiquitinated protein aggregates to the autophagy machinery.(1) This protein is able to polymerize via its N-terminal PB1 domain and to recognize polyubiquitin via its C-terminal UBA domain. It can also recruit the autophagosomal protein LC3 and co-localizes with many types of polyubiquitinated protein aggregates.(1) Here we discuss possible implications of these findings and raise some questions for further investigation.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Autophagy, mitochondrial quality control, and oncogenesis.

Cancer is a disease associated with aging. More than 80% of human cancers are diagnosed in people aged 55 years or older. Autophagy has recently been demonstrated to be a novel mechanism of tumor suppression. Interestingly, autophagy also plays an important role in the control of aging. Here we summarize the genetic studies of autophagy in tumorigenesis and aging, and propose that autophagy may suppress tumor development and prevent aging through a common mechanism involving mitochondrial surveillance.

Animals↗
PubMed2006

BID-deficient breast cancer MCF-7 cells as a model for the study of autophagy in cancer therapy.

The BH3-only death factors share just the short BH3 domain with the other Bcl-2 family subclasses. With the exception of BID, which might also bind to BAX, they are thought to act by binding to and neutralizing Bcl-2 like survival factors.(1) Camptothecin (CPT)-induced apoptosis in breast cancer MCF-7 cells is associated with activation of cathepsin B and aggregation of BAX and BID on mitochondria. BID knock down protects cancer cells against apoptosis and induces autophagy, manifested with increased expression of Beclin 1 and MAP1LC3. The compensatory increase in the concentration of Hrk (another member of the BH3-only protein family) and its co-localization with BCL-2 on organelles in BID(-) breast cancer cells has also been observed. Nonetheless, Hrk is not able to substitute for BID in triggering apoptosis. Its role in autophagy induction is also doubtful, since MAP1LC3 expression was equally high in BID(-)Hrk(-) and BID(-)Hrk(+) breast cancer cells exposed to CPT. We conclude that BID can serve as a molecular switch between apoptosis and autophagy. BID(+) and BID(-) breast cancer MCF-7 cells could be considered to be a useful model for the study of the molecular interdependences between apoptosis and autophagy and the role of both processes in cancer therapy.

Antineoplastic Agents, Phytogenic↗
PubMed2006

Detection of autophagy in tissue by standard immunohistochemistry: possibilities and limitations.

Transmission electron microscopy (TEM) is currently the standard method to monitor autophagy in tissue. Because TEM is labor intensive, we recently questioned whether marker proteins could be found for unambiguous detection of autophagy in tissue using standard immunohistochemical techniques. Our findings indicated that the identification of autophagy-specific biomarkers for tissue is highly compromised due to lack of differential gene expression. In this respect, TEM remains an indispensable technique for evaluation of autophagy in situ. Nevertheless, immunohistochemical staining of microtubule-associated protein 1 light chain 3 (LC3) appeared to be a valuable technique to detect autophagosome formation in tissue but only when this protein is overexpressed, e.g., in GFP-LC3 transgenic animals. Furthermore, demonstration of granular cytoplasmic ubiquitin inclusions by immunohistochemistry may be an attractive technique to measure autophagic cell degeneration in some human pathologies such as neurodegenerative diseases, heart failure and atherosclerosis.

Animals↗
PubMed2006

Tracker dyes to probe mitochondrial autophagy (mitophagy) in rat hepatocytes.

Mitochondria become targets for autophagic degradation after nutrient deprivation, a process also termed mitophagy. In this study, we used LysoTracker Red (LTR) and MitoTracker Green to characterize the kinetics of autophagosomal proliferation and mitophagy in cultured rat hepatocytes. Autophagy induced by nutrient deprivation plus glucagon increased LTR uptake assessed with a fluorescence plate reader and the number of LTR-labeled acidic organelles assessed with confocal microscopy in individual hepatocytes both by 4- to 6-fold. Serial imaging of hepatocytes coloaded with MitoTracker Green (MTG) revealed an average mitochondrial digestion time of 7.5 min after autophagic induction. In the presence of protease inhibitors, digestion time more than doubled, and the total number of LTR-labeled organelles increased about 40%, but the proportion of the LTR-labeled acidic organelles containing MTG fluorescence remained constant at about 75%. Autophagy inhibitors, 3-methyladenine, wortmannin and LY204002, suppressed the increase of LTR uptake after nutrient deprivation by up to 85%, confirming that increased LTR uptake reflected autophagy induction. Cyclosporin A and NIM811, specific inhibitors of the mitochondrial permeability transition (MPT), also decreased LTR uptake, whereas tacrolimus, an immunosuppressive reagent that does not inhibit the MPT, was without effect. In addition, the c-Jun N-terminal kinase (JNK) inhibitors, SCP25041 and SP600125, blocked LTR uptake by 47% and 61%, respectively, but ERK1, p38 and caspase inhibitors had no effect. The results show that mitochondria once selected for mitophagy are rapidly digested and support the concept that mitochondrial autophagy involves the MPT and signaling through PI3 kinase and possibly JNK.

Adenine↗
PubMed2006

Protective roles for induction of autophagy in multiple proteinopathies.

Many late-onset neurodegenerative diseases, including Parkinson's disease, tauopathies, Huntington's disease and forms of spinocerebellar ataxia, are caused by aggregate-prone proteins. Previously we showed that mutant huntingtin is an autophagy substrate and that autophagy induction reduced soluble and aggregated huntingtin levels and attenuated its toxicity in cell, fly and mouse models of disease. We have recently shown in cell and fly models that autophagy induction may have general protective effects across a range of diseases caused by aggregate-prone intracellular proteins. First, we showed that this strategy reduces the levels of the primary toxin, the aggregate-prone mutant protein. Second, our recent work suggests that autophagy induction may have additional cytoprotective effects by protecting cells against a range of subsequent pro-apoptotic insults.

Animals↗
PubMed2006

ALIS are stress-induced protein storage compartments for substrates of the proteasome and autophagy.

Misfolded proteins can be directed into cytoplasmic aggregates such as aggresomes and dendritic cell aggresome-like induced structures (DALIS). DALIS were originally identified in lipopolysaccharide-stimulated dendritic cells and act as storage compartments for polyubiquitinated Defective Ribosomal Products (DRiPs) prior to their clearance by the proteasome. Here we demonstrate that ubiquitinated protein aggregates that are similar to DALIS, and not related to aggresomes, can be observed in several cell types in response to stress, including oxidative stress, transfection, and starvation. Significantly, both immune and nonimmune cells could form these aggresome-like induced structures (ALIS). Protein synthesis was essential for ALIS formation in response to oxidative stress, indicating that DRiP formation was required. Furthermore, puromycin, which increases DRiP formation, was sufficient to induce ALIS formation. Inhibition of either proteasomes or of autophagy interfered with ALIS clearance in puromycin treated cells. Autophagy inhibition enhanced ALIS formation under a variety of stress conditions. During starvation, ALIS formation in autophagy-deficient cells was only partially inhibited by protein synthesis inhibitors, indicating that both long-lived proteins and DRiPs can be targeted to ALIS. Together, these findings demonstrate that ALIS act as generalized stress-induced protein storage compartments for substrates of the proteasome and autophagy.

Animals↗
PubMed2006

Autophagy: a highway for Porphyromonas gingivalis in endothelial cells.

P. gingivalis, an important periodontal pathogen associated with adult periodontitis and a likely contributing factor to atherosclerosis and cardiovascular disease, traffics in endothelial cells via the autophagic pathway. Initially, P. gingivalis rapidly adheres to the host cell surface followed by internalization via lipid rafts and incorporation of the bacterium into early phagosomes. P. gingivalis activates cellular autophagy to provide a replicative niche while suppressing apoptosis. The replicating vacuole contains host proteins delivered by autophagy that are used by this asaccharolytic pathogen to survive and replicate within the host cell. When autophagy is suppressed by 3-methyladenine or wortmannin, internalized P. gingivalis transits to the phagolysosome where it is destroyed and degraded. Therefore, the survival of P. gingivalis depends upon the activation of autophagy and survival of the endothelial host cell, but the mechanism by which P. gingivalis accomplishes this remains unclear.

Animals↗
PubMed2006

Autophagy in immune defense against Mycobacterium tuberculosis.

Autophagy is a newly recognized innate and adaptive immunity defense against intracellular pathogens, in keeping with its role as a cytoplasmic maintenance pathway. Induction of autophagy by physiological, pharmacological or immunological means can eliminate intracellular Mycobacterium tuberculosis, providing one of the first examples of the immunological role of autophagy. Under normal circumstances, M. Tuberculosis survives in macrophages by inhibiting phagolysosome biogenesis. Induction of autophagy overcomes the mycobacterial phagosome maturation block, and delivers the tubercle bacilli to degradative compartments where they are eliminated.

Autophagy↗
PubMed2006

Protective effect of autophagy in anoxia-reoxygenation of isolated cardiomyocyte?

Preconditioning and postconditioning increased numbers of living cells and decreased that of necrotic, apoptotic and autophagic cells in anoxia-reoxygenation of isolated cardiomyocytes. It was established that proteasome inhibitors prevented the necrotic and apoptotic cell death of cardiomyocytes in anoxia-reoxygenation and in such a way reproduce the effect of pharmacological preconditioning and postconditioning. In this case, the population of autophagic cardiomyocytes has not changed considerably or had a tendency of increasing compared to anoxia-reoxygenation. The data obtained showed that the specific protective effect of proteasome inhibitors could be caused by autophagy activation. In our recent experiments new data supporting this hypothesis were obtained. The inhibition of autophagy with N-3-methyladenine during anoxia-reoxygenation caused an increase in the number of necrotic cells and a decrease of the live cell population. Moreover, simultaneous inhibition of both autophagy and apoptosis (N-3-methyladenine and caspase-3 inhibitor application) in anoxia-reoxygenation led to a dramatic increase of necrotic cardiomyocytes and a concomitant decrease in the number of living cells. Thus, the process of autophagy in cardiomyocytes during anoxia-reoxygenation may lead not only to programmed cell death, but has also some protective effect. The mechanisms of this phenomenon are still in need of thorough investigation.

Adenine↗
PubMed2006

How a RING finger protein and a steroid hormone control autophagy.

Previous work in our laboratory has indicated that the steroid hormone ecdysone triggers programmed autophagy in the fat body of Drosophila larvae by downregulating the class I phosphoinositide 3-kinase (PI3K) pathway. We recently found evidence that Deep orange (Dor), a Drosophila RING finger protein implicated in late-endosomal trafficking, controls ecdysone signaling as well as autolysosome fusion, thus exerting a dual regulation of autophagy. We found that dor mutants are defective in programmed autophagy. The mutant larvae showed impaired upregulation of ecdysone signaling during development, accompanied by a failure to downregulate the PI3K pathway. Downregulation of the PI3K pathway could be restored by feeding the dor mutants with ecdysone. Even though ecdysone signaling and autophagy were impaired in the dor mutants, we detected an accumulation of autophagosomes in dor mutant fat bodies. This could probably be attributed to the failure of autophagosomes to fuse with lysosomes. In this Addendum we review these findings and provide some speculations about how Dor may control both ecdysone signalling and autolysosomal fusion.

Animals↗
PubMed2007

Autophagy and CD4+ T lymphocyte destruction by HIV-1.

The first step of HIV-1 infection is mediated by the binding of envelope glycoproteins (Env) to CD4 and two major coreceptors, CCR5 or CXCR4. The HIV-1 strains that use CCR5 are involved in primo-infection whereas those HIV-1 strains that use CXCR4 play a major role in the demise of CD4+ T lymphocytes and a rapid progression toward AIDS. Notably, binding of X4 Env expressed on cells to CXCR4 triggers apoptosis of uninfected CD4+ T cells. We now have just demonstrated that, independently of HIV-1 replication, transfected or HIV-1-infected cells that express X4 Env induce autophagy and accumulation of Beclin 1 in uninfected CD4+ T lymphocytes via CXCR4. Moreover, autophagy is a prerequisite to Env-induced apoptosis in uninfected bystander T cells, and CD4+ T cells still undergo an Env-mediated cell death with autophagic features when apoptosis is inhibited. To the best of our knowledge, these findings represent the first example of autophagy triggered through binding of virus envelope proteins to a cellular receptor, without viral replication, leading to apoptosis. Here, we proposed hypotheses about the significance of Env-induced Beclin 1 accumulation in CD4+ T cell death and about the role of autophagy in HIV-1 infected cells depending on the coreceptor involved.

Apoptosis Regulatory Proteins↗
PubMed2007

Caloric restriction and autophagy in Caenorhabditis elegans.

Autophagy is a catabolic process in which long-lived proteins and organelles are degraded for recycling in the cytoplasm. In the nematode Caenorhabditis elegans autophagy is associated with formation of the dauer larva, an alternative developmental stage that worms can enter under poor growth conditions. We have shown that C. elegans mutants that experience caloric restriction because they are feeding-defective also exhibit elevated autophagy and decreased levels of fat deposits, as well as smaller cells and, consequently, a smaller body size. Our results suggest novel relationships between caloric restriction, longevity, body size and autophagy.

Animals↗
PubMed2007

Autophagy of vascular smooth muscle cells in atherosclerotic lesions.

Autophagy genes were first identified in the yeast system and some of their mammalian orthologues have also been characterized. Increasing lines of evidence indicate that various intracellular proteins, including G proteins, mammalian target of rapamycin (mTor) and Pl3K/Akt/PKB, of transmembrane signaling pathways are involved in the regulation of autophagy genes. We have recently discovered autophagy as a mechanism of cell death in atherosclerotic vascular smooth muscle cells (VSMCs). Tumor necrosis factor-alpha (TNF-alpha), insulin-like growth factor-1 (IGF-1), and 7-ketocholesterol can regulate the expression of autophagic genes, including microtubule-associated protein 1 light chain-3 (MAP1LC3) and Beclin 1, through Akt/PKB and c-jun N-terminal signal pathways in VSMCs. However, the balance between cell death and survival of VSMCs in the fibrous cap of atherosclerotic plaques appears to best correlate with plaque instability. Understanding the underlying cellular and molecular mechanisms of autophagy can provide key insights into the cell death machinery of atherosclerotic diseases.

Apoptosis Regulatory Proteins↗
PubMed2007

Endoplasmic reticulum stress: a new pathway to induce autophagy.

Autophagy is a response to the stress of nutrient limitation in yeast, whereby cytosolic long-lived proteins and organelles are nonselectively degraded, and the resulting macromolecules are recycled to allow new protein synthesis that is essential for survival. We recently revealed that endoplasmic reticulum (ER) stress induces autophagy. When misfolded proteins accumulate in the ER the resulting stress activates the unfolded protein response (UPR) to induce the expression of chaperones and proteins involved in the recovery process. Under conditions of ER stress, the preautophagosomal structure is assembled, and transport of autophagosomes to the vacuole is stimulated in an Atg protein-dependent manner. Interestingly, Atg1 has high kinase activity during ER stress-induced autophagy similar to the situation in starvation-induced autophagy.

Autophagy↗