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Autophagy Aug 2021Different types of autophagy co-exist in all mammalian cells, however, the specific contribution of each of these autophagic pathways to the maintenance of cellular... (Review)
Review
Different types of autophagy co-exist in all mammalian cells, however, the specific contribution of each of these autophagic pathways to the maintenance of cellular proteostasis and cellular function remains unknown. In this work, we have investigated the consequences of failure of chaperone-mediated autophagy (CMA) in neurons and compared the impact, on the neuronal proteome, of CMA loss to that of macroautophagy loss. We found that these autophagic pathways are non-redundant and that CMA is the main one responsible for maintenance of the metastable proteome (the one at risk of aggregation). We demonstrate that loss of CMA, as the one that occurs in aging, has a synergistic effect with the proteotoxicity associated with neurodegenerative conditions such as Alzheimer disease (AD) and, conversely, that, pharmacological enhancement of CMA is effective in improving both behavior and pathology in two different AD mouse models.
Topics: Aging; Animals; Autophagy; Chaperone-Mediated Autophagy; Humans; Lysosomes; Neurons; Proteostasis
PubMed: 34110247
DOI: 10.1080/15548627.2021.1935007 -
Autophagy Apr 2019Helicobacter pylori (H. pylori) is a common human pathogenic bacterium. Once infected, it is difficult for the host to clear this organism using the innate immune...
Helicobacter pylori (H. pylori) is a common human pathogenic bacterium. Once infected, it is difficult for the host to clear this organism using the innate immune system. Increased antibiotic resistance further makes it challenging for effective eradication. However, the mechanisms of immune evasion still remain obscure, and novel strategies should be developed to efficiently eliminate H. pylori infection in stomachs. Here we uncovered desirable anti-H. pylori effect of vitamin D3 both in vitro and in vivo, even against antibiotic-resistant strains. We showed that H. pylori can invade into the gastric epithelium where they became sequestered and survived in autophagosomes with impaired lysosomal acidification. Vitamin D3 treatment caused a restored lysosomal degradation function by activating the PDIA3 receptor, thereby promoting the nuclear translocation of PDIA3-STAT3 protein complex and the subsequent upregulation of MCOLN3 channels, resulting in an enhanced Ca release from lysosomes and normalized lysosomal acidification. The recovered lysosomal degradation function drives H. pylori to be eliminated through the autolysosomal pathway. These findings provide a novel pathogenic mechanism on how H. pylori can survive in the gastric epithelium, and a unique pathway for vitamin D3 to reactivate the autolysosomal degradation function, which is critical for the antibacterial action of vitamin D3 both in cells and in animals, and perhaps further in humans. Abbreviations: 1,25D3: 1α, 25-dihydroxyvitamin D3; ATG5: autophagy related 5; Baf A1: bafilomycin A; BECN1: beclin 1; CagA: cytotoxin-associated gene A; CFU: colony-forming unit; ChIP-PCR: chromatin immunoprecipitation-polymerase chain reaction; Con A: concanamycin A; CQ: chloroquine; CRISPR: clustered regularly interspaced short palindromic repeats; CTSD: cathepsin D; GPN: Gly-Phe-β-naphthylamide; H. pylori: Helicobacter pylori; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCOLN1: mucolipin 1; MCOLN3: mucolipin 3; MCU: mitochondrial calcium uniporter; MOI: multiplicity of infection; NAGLU: N-acetyl-alpha-glucosaminidase; PDIA3: protein disulfide isomerase family A member 3; PMA: phorbol 12-myristate 13-acetate; PRKC: protein kinase C; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; SS1: Sydney Strain 1; TRP: transient receptor potential; VacA: vacuolating cytotoxin; VD3: vitamin D3; VDR: vitamin D receptor.
Topics: Acetylglucosaminidase; Acid Phosphatase; Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Autophagosomes; Autophagy; Autophagy-Related Protein 5; Calcium; Carrier Proteins; Cell Line; Cholecalciferol; Epithelial Cells; Helicobacter Infections; Helicobacter pylori; Humans; Lysosomes; Male; Mice, Inbred C57BL; Protein Disulfide-Isomerases; Receptors, Calcitriol; STAT3 Transcription Factor; Stomach; Transient Receptor Potential Channels; Cathelicidins
PubMed: 30612517
DOI: 10.1080/15548627.2018.1557835 -
Journal of the American Society of... May 2017Excessive fat intake contributes to the progression of metabolic diseases cellular injury and inflammation, a process termed lipotoxicity. Here, we investigated the...
Excessive fat intake contributes to the progression of metabolic diseases cellular injury and inflammation, a process termed lipotoxicity. Here, we investigated the role of lysosomal dysfunction and impaired autophagic flux in the pathogenesis of lipotoxicity in the kidney. In mice, a high-fat diet (HFD) resulted in an accumulation of phospholipids in enlarged lysosomes within kidney proximal tubular cells (PTCs). In isolated PTCs treated with palmitic acid, autophagic degradation activity progressively stagnated in association with impaired lysosomal acidification and excessive lipid accumulation. Pulse-chase experiments revealed that the accumulated lipids originated from cellular membranes. In mice with induced PTC-specific ablation of autophagy, PTCs of HFD-mice exhibited greater accumulation of ubiquitin-positive protein aggregates normally removed by autophagy than did PTCs of mice fed a normal diet. Furthermore, HFD-mice had no capacity to augment autophagic activity upon another pathologic stress. Autophagy ablation also exaggerated HFD-induced mitochondrial dysfunction and inflammasome activation. Moreover, renal ischemia-reperfusion induced greater injury in HFD-mice than in mice fed a normal diet, and ablation of autophagy further exacerbated this effect. Finally, we detected similarly enhanced phospholipid accumulation in enlarged lysosomes and impaired autophagic flux in the kidneys of obese patients compared with nonobese patients. These findings provide key insights regarding the pathophysiology of lipotoxicity in the kidney and clues to a novel treatment for obesity-related kidney diseases.
Topics: Animals; Autophagy; Diet, High-Fat; Kidney; Kidney Diseases; Lipid Metabolism; Lysosomes; Male; Mice; Palmitic Acid
PubMed: 27932476
DOI: 10.1681/ASN.2016070731 -
Cells Mar 2019The small GTPase, Rab7a, and the regulators of its GDP/GTP-binding status were shown to have roles in both endocytic membrane traffic and autophagy. Classically known to... (Review)
Review
The small GTPase, Rab7a, and the regulators of its GDP/GTP-binding status were shown to have roles in both endocytic membrane traffic and autophagy. Classically known to regulate endosomal retrograde transport and late endosome-lysosome fusion, earlier work has indicated a role for Rab7a in autophagosome-lysosome fusion as well as autolysosome maturation. However, as suggested by recent findings on PTEN-induced kinase 1 (PINK1)-Parkin-mediated mitophagy, Rab7a and its regulators are critical for the correct targeting of Atg9a-bearing vesicles to effect autophagosome formation around damaged mitochondria. This mitophagosome formation role for Rab7a is dependent on an intact Rab cycling process mediated by the Rab7a-specific guanine nucleotide exchange factor (GEF) and GTPase activating proteins (GAPs). Rab7a activity in this regard is also dependent on the retromer complex, as well as phosphorylation by the TRAF family-associated NF-κB activator binding kinase 1 (TBK1). Here, we discuss these recent findings and broadened perspectives on the role of the Rab7a network in PINK1-Parkin mediated mitophagy.
Topics: Animals; Humans; Lysosomes; Mitophagy; Models, Biological; Phagosomes; Phosphorylation; rab GTP-Binding Proteins
PubMed: 30857122
DOI: 10.3390/cells8030224 -
Current Biology : CB Apr 2015
Topics: Humans; Lysosomes
PubMed: 25898096
DOI: 10.1016/j.cub.2015.02.027 -
Cellular Physiology and Biochemistry :... May 2021The lysosome is a single ubiquitous membrane-enclosed intracellular organelle with an acidic pH present in all eukaryotic cells, which contains large numbers of... (Review)
Review
The lysosome is a single ubiquitous membrane-enclosed intracellular organelle with an acidic pH present in all eukaryotic cells, which contains large numbers of hydrolytic enzymes with their maximal enzymatic activity at a low pH (pH ≤ 5) such as proteases, nucleases, and phosphatases that are able to degrade extracellular and intracellular components. It is well known that lysosomes act as a center for degradation and recycling of large numbers of macromolecules delivered by endocytosis, phagocytosis, and autophagy. Lysosomes are recognized as key organelles for cellular clearance and are involved in many cellular processes and maintain cellular homeostasis. Recently, it has been shown that lysosome function and its related pathways are of particular importance in vascular regulation and related diseases. In this review, we highlighted studies that have improved our understanding of the connection between lysosome function and vascular physiological and pathophysiological activities in arterial smooth muscle cells (SMCs) and endothelial cells (ECs). Sphingolipids-metabolizingenzymes in lysosomes play critical roles in intracellular signaling events that influence cellular behavior and function in SMCs and ECs. The focus of this review will be to define the mechanism by which the lysosome contributes to cardiovascular regulation and diseases. It is believed that exploring the role of lysosomal function and its sphingolipid metabolism in the initiation and progression of vascular disease and regulation may provide novel insights into the understanding of vascular pathobiology and helps develop more effective therapeutic strategies for vascular diseases.
Topics: Animals; Cardiovascular Diseases; Endothelial Cells; Humans; Lysosomes; Myocytes, Smooth Muscle; Sphingolipids
PubMed: 34019755
DOI: 10.33594/000000373 -
Cells May 2023Physiologically, autophagy is an evolutionarily conserved and self-degradative process in cells. Autophagy carries out normal physiological roles throughout mammalian... (Review)
Review
Physiologically, autophagy is an evolutionarily conserved and self-degradative process in cells. Autophagy carries out normal physiological roles throughout mammalian life. Accumulating evidence shows autophagy as a mechanism for cellular growth, development, differentiation, survival, and homeostasis. In male reproductive systems, normal spermatogenesis and steroidogenesis need a balance between degradation and energy supply to preserve cellular metabolic homeostasis. The main process of autophagy includes the formation and maturation of the phagophore, autophagosome, and autolysosome. Autophagy is controlled by a group of autophagy-related genes that form the core machinery of autophagy. Three types of autophagy mechanisms have been discovered in mammalian cells: macroautophagy, microautophagy, and chaperone-mediated autophagy. Autophagy is classified as non-selective or selective. Non-selective macroautophagy randomly engulfs the cytoplasmic components in autophagosomes that are degraded by lysosomal enzymes. While selective macroautophagy precisely identifies and degrades a specific element, current findings have shown the novel functional roles of autophagy in male reproduction. It has been recognized that dysfunction in the autophagy process can be associated with male infertility. Overall, this review provides an overview of the cellular and molecular basics of autophagy and summarizes the latest findings on the key role of autophagy in mammalian male reproductive physiology.
Topics: Animals; Male; Macroautophagy; Autophagy; Autophagosomes; Microautophagy; Lysosomes; Mammals
PubMed: 37174722
DOI: 10.3390/cells12091322 -
The Journal of Biological Chemistry Apr 2018Ubiquitination is a widespread post-translational modification that controls multiple steps in autophagy, a major lysosome-mediated intracellular degradation pathway. A... (Review)
Review
Ubiquitination is a widespread post-translational modification that controls multiple steps in autophagy, a major lysosome-mediated intracellular degradation pathway. A variety of ubiquitin chains are attached as selective labels on protein aggregates and dysfunctional organelles, thus promoting their autophagy-dependent degradation. Moreover, ubiquitin modification of autophagy regulatory components is essential to positively or negatively regulate autophagy flux in both non-selective and selective pathways. We review the current findings that elucidate the components, timing, and kinetics of the multivalent role of ubiquitin signals in control of amplitude and selectivity of autophagy pathways as well as their impact on the development of human diseases.
Topics: Animals; Humans; Lysosomes; Protein Aggregates; Proteolysis; Signal Transduction; Ubiquitin; Ubiquitination
PubMed: 29187595
DOI: 10.1074/jbc.TM117.000117 -
Trends in Molecular Medicine Jan 2020Cellular function requires coordination between different organelles and metabolic cues. Mitochondria and lysosomes are essential for cellular metabolism as major... (Review)
Review
Cellular function requires coordination between different organelles and metabolic cues. Mitochondria and lysosomes are essential for cellular metabolism as major contributors of chemical energy and building blocks. It is therefore pivotal for cellular function to coordinate the metabolic roles of mitochondria and lysosomes. However, these organelles do more than metabolism, given their function as fundamental signaling platforms in the cell that regulate many key processes such as autophagy, proliferation, and cell death. Mechanisms of crosstalk between mitochondria and lysosomes are discussed, both under physiological conditions and in diseases that affect these organelles.
Topics: Animals; Autophagy; Cell Death; Cell Proliferation; Humans; Lysosomes; Metabolic Networks and Pathways; Mitochondria; Neurodegenerative Diseases; Signal Transduction
PubMed: 31791731
DOI: 10.1016/j.molmed.2019.10.009 -
Frontiers in Immunology 2021Autophagy is a vital conserved degradative process that maintains cellular homeostasis by recycling or eliminating dysfunctional cellular organelles and proteins. More... (Review)
Review
Autophagy is a vital conserved degradative process that maintains cellular homeostasis by recycling or eliminating dysfunctional cellular organelles and proteins. More recently, autophagy has become a well-recognized host defense mechanism against intracellular pathogens through a process known as xenophagy. On the host-microbe battlefield many intracellular bacterial pathogens have developed the ability to subvert xenophagy to establish infection. Obligately intracellular bacterial pathogens of the family, including , and have developed a dichotomous strategy to exploit the host autophagic pathway to obtain nutrients while escaping lysosomal destruction for intracellular survival within the host cell. In this review, the recent findings regarding how these master manipulators engage and inhibit autophagy for infection are explored. Future investigation to understand mechanisms used by to exploit autophagy may advance novel antimicrobial therapies and provide new insights into how intracellular microbes exploit autophagy to survive.
Topics: Anaplasmataceae; Anaplasmataceae Infections; Animals; Autophagy; Host Microbial Interactions; Humans; Immunity, Innate; Lysosomes; Signal Transduction; Wnt Signaling Pathway
PubMed: 33912170
DOI: 10.3389/fimmu.2021.642771