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Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.Nature Communications Apr 2021Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau...
Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression.
Topics: Acetylation; Animals; Brain; Chaperone-Mediated Autophagy; Female; Humans; Male; Mice; Mice, Inbred C57BL; Neurons; Tauopathies; tau Proteins
PubMed: 33854069
DOI: 10.1038/s41467-021-22501-9 -
Cells Oct 2019Hepatitis C virus (HCV) infection triggers autophagy processes, which help clear out the dysfunctional viral and cellular components that would otherwise inhibit the... (Review)
Review
Hepatitis C virus (HCV) infection triggers autophagy processes, which help clear out the dysfunctional viral and cellular components that would otherwise inhibit the virus replication. Increased cellular autophagy may kill the infected cell and terminate the infection without proper regulation. The mechanism of autophagy regulation during liver disease progression in HCV infection is unclear. The autophagy research has gained a lot of attention recently since autophagy impairment is associated with the development of hepatocellular carcinoma (HCC). Macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) are three autophagy processes involved in the lysosomal degradation and extracellular release of cytosolic cargoes under excessive stress. Autophagy processes compensate for each other during extreme endoplasmic reticulum (ER) stress to promote host and microbe survival as well as HCC development in the highly stressed microenvironment of the cirrhotic liver. This review describes the molecular details of how excessive cellular stress generated during HCV infection activates CMA to improve cell survival. The pathological implications of stress-related CMA activation resulting in the loss of hepatic innate immunity and tumor suppressors, which are most often observed among cirrhotic patients with HCC, are discussed. The oncogenic cell programming through autophagy regulation initiated by a cytoplasmic virus may facilitate our understanding of HCC mechanisms related to non-viral etiologies and metabolic conditions such as uncontrolled type II diabetes. We propose that a better understanding of how excessive cellular stress leads to cancer through autophagy modulation may allow therapeutic development and early detection of HCC.
Topics: Autophagy; Carcinoma, Hepatocellular; Cell Survival; Chaperone-Mediated Autophagy; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Stress; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Hepatocytes; Humans; Interferon-alpha; Liver; Liver Neoplasms; Lysosomes; NF-E2-Related Factor 2; Receptor, Interferon alpha-beta; Signal Transduction; Tumor Microenvironment; Virus Replication
PubMed: 31652893
DOI: 10.3390/cells8111308 -
Cells Apr 2020Microautophagy is a type of autophagy. It is characterized by direct enclosing with the vacuolar/lysosomal membrane, which completes the isolation and uptake of cell... (Review)
Review
Microautophagy is a type of autophagy. It is characterized by direct enclosing with the vacuolar/lysosomal membrane, which completes the isolation and uptake of cell components in the vacuole. Several publications present evidence that plants exhibit microautophagy. Plant microautophagy is involved in anthocyanin accumulation in the vacuole, eliminating damaged chloroplasts and degrading cellular components during starvation. However, information on the molecular mechanism of microautophagy is less available than that on the general macroautophagy, because the research focusing on microautophagy has not been widely reported. In yeast and animals, it is suggested that microautophagy can be classified into several types depending on morphology and the requirements of autophagy-related () genes. This review summarizes the studies on plant microautophagy and discusses possible techniques for a future study in this field while taking into account the information on microautophagy obtained from yeast and animals.
Topics: Animals; Microautophagy; Models, Biological; Plant Proteins; Plants; Saccharomyces cerevisiae
PubMed: 32260410
DOI: 10.3390/cells9040887 -
Biomolecules Dec 2022Atherosclerosis (AS) is a lipid-driven disorder of the artery intima characterized by the equilibrium between inflammatory and regressive processes. A protein complex... (Review)
Review
Atherosclerosis (AS) is a lipid-driven disorder of the artery intima characterized by the equilibrium between inflammatory and regressive processes. A protein complex called NLRP3 inflammasome is involved in the release of mature interleukin-1β (IL-1β), which is connected to the initiation and progression of atherosclerosis. Autophagy, which includes macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy, is generally recognized as the process by which cells transfer their constituents to lysosomes for digestion. Recent studies have suggested a connection between vascular inflammation and autophagy. This review summarizes the most recent studies and the underlying mechanisms associated with different autophagic pathways and NLRP3 inflammasomes in vascular inflammation, aiming to provide additional evidence for atherosclerosis research.
Topics: Humans; Inflammasomes; Plaque, Atherosclerotic; NLR Family, Pyrin Domain-Containing 3 Protein; Autophagy; Atherosclerosis; Inflammation
PubMed: 36671400
DOI: 10.3390/biom13010015 -
Current Opinion in Lipidology Jun 2018Intracellular lipid metabolism is a complex interplay of exogenous lipid handling, trafficking, storage, lipolysis, and export. Recent work has implicated the cellular... (Review)
Review
PURPOSE OF REVIEW
Intracellular lipid metabolism is a complex interplay of exogenous lipid handling, trafficking, storage, lipolysis, and export. Recent work has implicated the cellular degradative process called autophagy in several aspects of lipid metabolism. We will discuss both the classical and novel roles of autophagy and the autophagic machinery in this setting.
RECENT FINDINGS
The delivery of lipid droplets to lysosomes for hydrolysis, named lipophagy, was the first described functional role for autophagy in lipid metabolism. The molecular machinery and regulation of this selective form of macroautophagy is beginning to be discovered and has the potential to shed enormous light on intracellular lipolysis. Yet, the autophagic machinery appears to also be coopted for alternative roles that include interaction with cytosolic lipolysis pathways, supply and expansion of lipid droplets, and lipoprotein trafficking. Additionally, lesser studied forms of autophagy called microautophagy and chaperone-mediated autophagy have distinct roles in lipid handling that also intersect with classical macroautophagy. The integration of current knowledge in these areas into a holistic understanding of intracellular lipid metabolism will be a goal of this review.
SUMMARY
As the field of autophagy has evolved and expanded to include functional roles in various aspects of cellular degradation, so has its role in intracellular lipid metabolism. Understanding the mechanisms underlying these classical and alternative roles of autophagy will not only enhance our knowledge in lipid biology but also provide new avenues of translation to human lipid disorders.
Topics: Animals; Autophagy; Humans; Lipid Droplets; Lipid Metabolism Disorders; Lipolysis; Lipoproteins; Lysosomes; Protein Transport
PubMed: 29601311
DOI: 10.1097/MOL.0000000000000509 -
Autophagy Oct 2020Selective autophagy is critical for the regulation of cellular homeostasis in organisms from yeast to humans. This process is a specific degradation pathway for a wide...
UNLABELLED
Selective autophagy is critical for the regulation of cellular homeostasis in organisms from yeast to humans. This process is a specific degradation pathway for a wide variety of substrates including unwanted cytosolic components, such as protein aggregates, damaged and/or superfluous organelles, and pathogens. However, it has been less clear as to whether a protein complex or substructure of an organelle can be targeted for removal by selective autophagy. One example of such a substrate is the nuclear pore complex (NPC), a large macromolecular assembly that is present throughout the nuclear envelope. Here, we highlight two recent studies that demonstrate for the first time that NPCs are targeted for vacuolar degradation through selective autophagy.
ABBREVIATIONS
AIM: Atg8-interacting motif; NE: nuclear envelope; NPC: nuclear pore complex; Nup: nucleoporin; PMN/micronucleophagy: piecemeal microautophagy of the nucleus.
Topics: Autophagy; Cell Nucleus; Cytosol; Macroautophagy; Nuclear Envelope; Nuclear Pore; Nuclear Pore Complex Proteins; Organelles; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Vacuoles
PubMed: 32713250
DOI: 10.1080/15548627.2020.1798199 -
Philosophical Transactions of the Royal... Mar 2010Cells need a constant supply of precursors to enable the production of macromolecules to sustain growth and survival. Unlike metazoans, unicellular eukaryotes depend... (Review)
Review
Cells need a constant supply of precursors to enable the production of macromolecules to sustain growth and survival. Unlike metazoans, unicellular eukaryotes depend exclusively on the extracellular medium for this supply. When environmental nutrients become depleted, existing cytoplasmic components will be catabolized by (macro)autophagy in order to re-use building blocks and to support ATP production. In many cases, autophagy takes care of cellular housekeeping to sustain cellular viability. Autophagy encompasses a multitude of related and often highly specific processes that are implicated in both biogenetic and catabolic processes. Recent data indicate that in some unicellular eukaryotes that undergo profound differentiation during their life cycle (e.g. kinetoplastid parasites and amoebes), autophagy is essential for the developmental change that allows the cell to adapt to a new host or form spores. This review summarizes the knowledge on the molecular mechanisms of autophagy as well as the cytoplasm-to-vacuole-targeting pathway, pexophagy, mitophagy, ER-phagy, ribophagy and piecemeal microautophagy of the nucleus, all highly selective forms of autophagy that have first been uncovered in yeast species. Additionally, a detailed analysis will be presented on the state of knowledge on autophagy in non-yeast unicellular eukaryotes with emphasis on the role of this process in differentiation.
Topics: Autophagy; Cell Nucleus; Cytoplasm; Dictyostelium; Endoplasmic Reticulum; Entamoeba; Eukaryota; Leishmania; Models, Biological; Peroxisomes; Phagosomes; Ribosomes; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Trypanosoma; Vacuoles
PubMed: 20124347
DOI: 10.1098/rstb.2009.0237 -
Biomolecules & Therapeutics Jul 2021The gastrointestinal (GI) tract is a series of hollow organs that is responsible for the digestion and absorption of ingested foods and the excretion of waste. Any... (Review)
Review
The gastrointestinal (GI) tract is a series of hollow organs that is responsible for the digestion and absorption of ingested foods and the excretion of waste. Any changes in the GI tract can lead to GI disorders. GI disorders are highly prevalent in the population and account for substantial morbidity, mortality, and healthcare utilization. GI disorders can be functional, or organic with structural changes. Functional GI disorders include functional dyspepsia and irritable bowel syndrome. Organic GI disorders include inflammation of the GI tract due to chronic infection, drugs, trauma, and other causes. Recent studies have highlighted a new explanatory mechanism for GI disorders. It has been suggested that autophagy, an intracellular homeostatic mechanism, also plays an important role in the pathogenesis of GI disorders. Autophagy has three primary forms: macroautophagy, microautophagy, and chaperone-mediated autophagy. It may affect intestinal homeostasis, host defense against intestinal pathogens, regulation of the gut microbiota, and innate and adaptive immunity. Drugs targeting autophagy could, therefore, have therapeutic potential for treating GI disorders. In this review, we provide an overview of current understanding regarding the evidence for autophagy in GI diseases and updates on potential treatments, including drugs and complementary and alternative medicines.
PubMed: 34127572
DOI: 10.4062/biomolther.2021.086 -
International Journal of Molecular... Mar 2021Historically, studies of intracellular membrane trafficking have focused on the secretory and endocytic pathways and their major organelles. However, these pathways are... (Review)
Review
Historically, studies of intracellular membrane trafficking have focused on the secretory and endocytic pathways and their major organelles. However, these pathways are also directly implicated in the biogenesis and function of other important intracellular organelles, the best studied of which are peroxisomes and lipid droplets. There is a large recent body of work on these organelles, which have resulted in the introduction of new paradigms regarding the roles of membrane trafficking organelles. In this review, we discuss the roles of membrane trafficking in the life cycle of lipid droplets. This includes the complementary roles of lipid phase separation and proteins in the biogenesis of lipid droplets from endoplasmic reticulum (ER) membranes, and the attachment of mature lipid droplets to membranes by lipidic bridges and by more conventional protein tethers. We also discuss the catabolism of neutral lipids, which in part results from the interaction of lipid droplets with cytosolic molecules, but with important roles for both macroautophagy and microautophagy. Finally, we address their eventual demise, which involves interactions with the autophagocytotic machinery. We pay particular attention to the roles of small GTPases, particularly Rab18, in these processes.
Topics: Animals; Autophagy; Biological Transport; Endoplasmic Reticulum; Humans; Intracellular Membranes; Lipid Droplets; rab GTP-Binding Proteins
PubMed: 33803444
DOI: 10.3390/ijms22052776 -
Frontiers in Oncology 2020Chaperone-mediated autophagy (CMA) represents a specific way of lysosomal protein degradation and contrary to macro and microautophagy is independent of vesicles... (Review)
Review
Chaperone-mediated autophagy (CMA) represents a specific way of lysosomal protein degradation and contrary to macro and microautophagy is independent of vesicles formation. The role of CMA in different physiopathological processes has been studied for several years. In cancer, alterations of the CMA principal components, Hsc70 and Lamp2A protein and mRNA levels, have been described in malignant cells. However, changes in the expression levels of these CMA components are not always associated with changes in CMA activity and their biological significance must be carefully interpreted case by case. The objective of this review is to discuss whether altering the CMA activity, CMA substrates or CMA components is accurate to avoid cancer progression. In particular, this review will discuss about the evidences in which alterations CMA components Lamp2A and Hsc70 are associated or not with changes in CMA activity in different cancer types. This analysis will help to better understand the role of CMA activity in cancer and to elucidate whether CMA can be considered as target for therapeutics. Further, it will help to define whether the attention of the investigation should be focused on Lamp2A and Hsc70 because they can have an independent role in cancer progression beyond of their participation in altered CMA activity.
PubMed: 33643916
DOI: 10.3389/fonc.2020.614677