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Trends in Cell Biology Aug 2019Lysosomes are acidic and degradative organelles that receive and digest a plethora of molecular and particulate cargo delivered by endocytosis, autophagy, and... (Review)
Review
Lysosomes are acidic and degradative organelles that receive and digest a plethora of molecular and particulate cargo delivered by endocytosis, autophagy, and phagocytosis. The mechanisms responsible for sorting, transporting, and ultimately delivering membranes and cargo to lysosomes through fusion have been intensely investigated. Much less is understood about lysosome fission, which is necessary to balance the incessant flow of cargo into lysosomes and maintain steady-state number, size, and function of lysosomes. Here, we review the emerging picture of how lipid signals, coat and adaptor proteins, and motor-cytoskeletal assemblies drive budding, tubulation, splitting, and 'kiss-and-run' events that enable fission and exit from lysosomes and related organelles.
Topics: Animals; Humans; Lysosomes
PubMed: 31171420
DOI: 10.1016/j.tcb.2019.05.003 -
Frontiers in Immunology 2023
Topics: Humans; Peptide Hydrolases; Lysosomes; Neoplasms
PubMed: 36999043
DOI: 10.3389/fimmu.2023.1176736 -
Biochimica Et Biophysica Acta.... Sep 2020Neuronal ceroid lipofuscinoses, also collectively known as Batten disease, are a group of rare monogenic disorders caused by mutations in at least 13 different genes.... (Review)
Review
Neuronal ceroid lipofuscinoses, also collectively known as Batten disease, are a group of rare monogenic disorders caused by mutations in at least 13 different genes. They are characterized by the accumulation of lysosomal storage material and progressive neurological deterioration with dementia, epilepsy, retinopathy, motor disturbances, and early death [1]. Although the identification of disease-causing genes provides an important step for understanding the molecular mechanisms underlying neuronal ceroid lipofuscinoses, compared to other diseases, obstacles to the development of therapies for these rare diseases include less extensive physiopathology knowledge, limited number of patients to test treatments, and poor commercial interest from the industry. Current therapeutic strategies include enzyme replacement therapies, gene therapies targeting the brain and the eye, cell therapies, and pharmacological drugs that could modulate defective molecular pathways. In this review, we will focus in the emerging therapies based in the identification of small-molecules. Recent advances in high- throughput and high-content screening (HTS and HCS) using relevant cell-based assays and applying automation and imaging analysis algorithms, will allow the screening of a large number of compounds in lesser time. These approaches are particularly useful for drug repurposing for Batten disease, that takes the advantage to search for compounds that have already been tested in humans, thereby reducing significantly the resources needed for translation to clinics.
Topics: Algorithms; Animals; Humans; Lysosomes; Mutation; Neuronal Ceroid-Lipofuscinoses; Small Molecule Libraries
PubMed: 31521819
DOI: 10.1016/j.bbadis.2019.165553 -
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 -
Proceedings of the National Academy of... Jun 2022Macroautophagy promotes cellular homeostasis by delivering cytoplasmic constituents to lysosomes for degradation [Mizushima, 20, 521-527 (2018)]. However, while most...
Macroautophagy promotes cellular homeostasis by delivering cytoplasmic constituents to lysosomes for degradation [Mizushima, 20, 521-527 (2018)]. However, while most studies have focused on the mechanisms of protein degradation during this process, we report here that macroautophagy also depends on glycan degradation via the glycosidase, α-l-fucosidase 1 (FUCA1), which removes fucose from glycans. We show that cells lacking FUCA1 accumulate lysosomal glycans, which is associated with impaired autophagic flux. Moreover, in a mouse model of fucosidosis-a disease characterized by inactivating mutations in [Stepien , 11, E1383 (2020)]-glycan and autophagosome/autolysosome accumulation accompanies tissue destruction. Mechanistically, using lectin capture and mass spectrometry, we identified several lysosomal enzymes with altered fucosylation in FUCA1-null cells. Moreover, we show that the activity of some of these enzymes in the absence of FUCA1 can no longer be induced upon autophagy stimulation, causing retardation of autophagic flux, which involves impaired autophagosome-lysosome fusion. These findings therefore show that dysregulated glycan degradation leads to defective autophagy, which is likely a contributing factor in the etiology of fucosidosis.
Topics: Animals; Fucosidosis; Lysosomes; Macroautophagy; Mice; Polysaccharides; alpha-L-Fucosidase
PubMed: 35737835
DOI: 10.1073/pnas.2111506119 -
The FEBS Journal Apr 2022Endocytosis is an essential cellular process required for multiple physiological functions, including communication with the extracellular environment, nutrient uptake,... (Review)
Review
Endocytosis is an essential cellular process required for multiple physiological functions, including communication with the extracellular environment, nutrient uptake, and signaling by the cell surface receptors. In a broad sense, endocytosis is accomplished through either constitutive or ligand-induced invagination of the plasma membrane, which results in the formation of the plasma membrane-retrieved endocytic vesicles, which can either be sent for degradation to the lysosomes or recycled back to the PM. This additional function of endocytosis in membrane retrieval has been adopted by excitable cells, such as neurons, for membrane equilibrium maintenance at synapses. The last two decades were especially productive with respect to the identification of brain-specific functions of the endocytic machinery, which additionally include but not limited to regulation of neuronal differentiation and migration, maintenance of neuron morphology and synaptic plasticity, and prevention of neurotoxic aggregates spreading. In this review, we highlight the current knowledge of brain-specific functions of endocytic machinery with a specific focus on three brain cell types, neuronal progenitor cells, neurons, and glial cells.
Topics: Brain; Cell Membrane; Endocytosis; Lysosomes; Synapses
PubMed: 33896112
DOI: 10.1111/febs.15897 -
Autophagy Oct 2021Autophagy summarizes evolutionarily conserved, intracellular degradation processes targeting cytoplasmic material for lysosomal degradation. These encompass constitutive... (Review)
Review
Autophagy summarizes evolutionarily conserved, intracellular degradation processes targeting cytoplasmic material for lysosomal degradation. These encompass constitutive processes as well as stress responses, which are often found dysregulated in diseases. Autophagy pathways help in the clearance of damaged organelles, protein aggregates and macromolecules, mediating their recycling and maintaining cellular homeostasis. Protein-protein interaction networks contribute to autophagosome biogenesis, substrate loading, vesicular trafficking and fusion, protein translocations across membranes and degradation in lysosomes. Hypothesis-free proteomic approaches tremendously helped in the functional characterization of protein-protein interactions to uncover molecular mechanisms regulating autophagy. In this review, we elaborate on the importance of understanding protein-protein-interactions of varying affinities and on the strengths of mass spectrometry-based proteomic approaches to study these, generating new mechanistic insights into autophagy regulation. We discuss in detail affinity purification approaches and recent developments in proximity labeling coupled to mass spectrometry, which uncovered molecular principles of autophagy mechanisms.: AMPK: AMP-activated protein kinase; AP-MS: affinity purification-mass spectrometry; APEX2: ascorbate peroxidase-2; ATG: autophagy related; BioID: proximity-dependent biotin identification; ER: endoplasmic reticulum; GFP: green fluorescent protein; iTRAQ: isobaric tag for relative and absolute quantification; MS: mass spectrometry; PCA: protein-fragment complementation assay; PL-MS: proximity labeling-mass spectrometry; PtdIns3P: phosphatidylinositol-3-phosphate; PTM: posttranslational modification; PUP-IT: pupylation-based interaction tagging; RFP: red fluorescent protein; SILAC: stable isotope labeling by amino acids in cell culture; TAP: tandem affinity purification; TMT: tandem mass tag.
Topics: Autophagy; Lysosomes; Mass Spectrometry; Protein Interaction Maps; Proteomics
PubMed: 33183148
DOI: 10.1080/15548627.2020.1847461 -
FEBS Letters Jan 2024Autophagy is an intracellular catabolic process that eliminates cytoplasmic constituents selectively by tight engulfment in an isolation membrane or recycles bulk... (Review)
Review
Autophagy is an intracellular catabolic process that eliminates cytoplasmic constituents selectively by tight engulfment in an isolation membrane or recycles bulk cytoplasm by nonselective sequestration. Completion of the isolation membrane forms a double membrane vesicle, termed autophagosome, that proceeds to fusion with the lysosome, where the inner membrane and its cytoplasmic content are degraded. Autophagosome biogenesis is unique in that the newly-formed membrane, termed phagophore, is elongated by direct lipid flow from a proximal ER-associated donor membrane. Recent years mark a tremendous advancement in delineating the direct regulation of this process by different lipid species and associated protein complexes. Here we schematically summarize the current view of autophagy and autophagosome biogenesis.
Topics: Autophagy; Autophagosomes; Lysosomes; Lipids
PubMed: 37326419
DOI: 10.1002/1873-3468.14679 -
Biochimica Et Biophysica Acta.... Sep 2020The Neuronal Ceroid Lipofuscinoses (NCL), otherwise known as Batten disease, are a group of neurodegenerative diseases caused by mutations in 13 known genes. All except... (Review)
Review
The Neuronal Ceroid Lipofuscinoses (NCL), otherwise known as Batten disease, are a group of neurodegenerative diseases caused by mutations in 13 known genes. All except one NCL is autosomal recessive in inheritance, with similar aetiology and characterised by the accumulation of autofluorescent storage material in the lysosomes of cells. Age of onset and the rate of progression vary between the NCLs. They are collectively one of the most common lysosomal storage diseases, but the enigma remains of how genetically distinct diseases result in such remarkably similar pathogenesis. Much has been learnt from cellular studies about the function of the proteins encoded by the affected genes. Such research has utilised primitive unicellular models such as yeast and amoeba containing gene orthologues, cells derived from naturally occurring (sheep) and genetically engineered (mouse) animal models or patient-derived cells. Most recently, patient-derived induced pluripotent stem cell (iPSC) lines have been differentiated into neural cell-types to study molecular pathogenesis in the cells most profoundly affected by disease. Here, we review how cell models have informed much of the biochemical understanding of the NCLs and how more complex models are being used to further this understanding and potentially act as platforms for therapeutic efficacy studies in the future.
Topics: Animals; Disease Models, Animal; Humans; Lysosomes; Models, Biological; Neuronal Ceroid-Lipofuscinoses
PubMed: 31655107
DOI: 10.1016/j.bbadis.2019.165559 -
Cell Apr 2020In addition to their well-defined recycling function, lysosomes act as metabolic signaling hubs that adjust cellular metabolism according to the availability of...
In addition to their well-defined recycling function, lysosomes act as metabolic signaling hubs that adjust cellular metabolism according to the availability of nutrients and growth factors by regulating metabolic kinases and transcription factors on their surface. Moreover, lysosomal hydrolases and ions released to cytosol or extracellular space have recently emerged as important regulators of various cellular processes from cell death to cell division. To view this SnapShot, open or download the PDF.
Topics: Autophagy; Cytosol; Extracellular Space; Humans; Hydrolases; Lysosomes; Phosphotransferases; Signal Transduction; Transcription Factors
PubMed: 32359442
DOI: 10.1016/j.cell.2020.03.043