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Free Radical Biology & Medicine Aug 2012Current viewpoints concerning the bactericidal mechanisms of neutrophils are reviewed from a perspective that emphasizes challenges presented by the inability to... (Review)
Review
Current viewpoints concerning the bactericidal mechanisms of neutrophils are reviewed from a perspective that emphasizes challenges presented by the inability to duplicate ex vivo the intracellular milieu. Among the challenges considered are the influences of confinement upon substrate availability and reaction dynamics, direct and indirect synergistic interactions between individual toxins, and bacterial responses to stressors. Approaches to gauging relative contributions of various oxidative and nonoxidative toxins within neutrophils using bacteria and bacterial mimics as intrinsic probes are also discussed.
Topics: Animals; Escherichia coli; Host-Pathogen Interactions; Humans; Immunity, Innate; Neutrophils; Oxidation-Reduction; Phagosomes; Reactive Oxygen Species; Staphylococcus aureus
PubMed: 22609248
DOI: 10.1016/j.freeradbiomed.2012.05.008 -
Genes Jan 2023is the enteric protozoan parasite responsible for amebiasis. Trophozoites of ingest human cells in the intestine and other organs, which is the hallmark of its... (Review)
Review
is the enteric protozoan parasite responsible for amebiasis. Trophozoites of ingest human cells in the intestine and other organs, which is the hallmark of its pathogenesis. Phagocytosis and trogocytosis are pivotal biological functions for its virulence and also contribute to the proliferation of nutrient uptake from the environment. We previously elucidated the role of a variety of proteins associated with phagocytosis and trogocytosis, including Rab small GTPases, Rab effectors, including retromer, phosphoinositide-binding proteins, lysosomal hydrolase receptors, protein kinases, and cytoskeletal proteins. However, a number of proteins involved in phagocytosis and trogocytosis remain to be identified, and mechanistic details of their involvement must be elucidated at the molecular level. To date, a number of studies in which a repertoire of proteins associated with phagosomes and potentially involved in phagocytosis have been conducted. In this review, we revisited all phagosome proteome studies we previously conducted in order to reiterate information on the proteome of phagosomes. We demonstrated the core set of constitutive phagosomal proteins and also the set of phagosomal proteins recruited only transiently or in condition-dependent fashions. The catalogs of phagosome proteomes resulting from such analyses can be a useful source of information for future mechanistic studies as well as for confirming or excluding a possibility of whether a protein of interest in various investigations is likely or is potentially involved in phagocytosis and phagosome biogenesis.
Topics: Humans; Entamoeba histolytica; Proteome; Proteomics; Phagocytosis; Phagosomes; rab GTP-Binding Proteins
PubMed: 36833306
DOI: 10.3390/genes14020379 -
Molecular Microbiology Jan 2023Mammalian professional phagocytic cells ingest and kill invading microorganisms and prevent the development of bacterial infections. Our understanding of the sequence of...
Mammalian professional phagocytic cells ingest and kill invading microorganisms and prevent the development of bacterial infections. Our understanding of the sequence of events that results in bacterial killing and permeabilization in phagosomes is still largely incomplete. In this study, we used the Dictyostelium discoideum amoeba as a model phagocyte to study the fate of the bacteria Klebsiella pneumoniae inside phagosomes. Our analysis distinguishes three consecutive phases: bacteria first lose their ability to divide (killing), then their cytosolic content is altered (permeabilization), and finally their DNA is degraded (digestion). Phagosomal acidification and production of free radicals are necessary for rapid killing, membrane-permeabilizing proteins BpiC and AlyL are required for efficient permeabilization. These results illustrate how a combination of genetic and microscopical tools can be used to finely dissect the molecular events leading to bacterial killing and permeabilization in a maturing phagosome.
Topics: Animals; Dictyostelium; Phagosomes; Klebsiella pneumoniae; Membrane Proteins; Bacteria; Mammals
PubMed: 36416195
DOI: 10.1111/mmi.15004 -
The FEBS Journal Jun 2010Mycobacterium tuberculosis H(37)Rv is a highly successful pathogen and its success fully relies on its ability to utilize macrophages for its replication and, more... (Review)
Review
Mycobacterium tuberculosis H(37)Rv is a highly successful pathogen and its success fully relies on its ability to utilize macrophages for its replication and, more importantly, the macrophage should remain viable to host the Mycobacterium. Despite the fact that these phagocytes are usually very effective in internalizing and clearing most of the bacteria, M. tuberculosis H(37)Rv has evolved a number of very effective survival strategies, including: (a) the inhibition of phagosome-lysosome fusion; (b) the inhibition of phagosome acidification; (c) the recruitment and retention of tryptophan-aspartate containing coat protein on phagosomes to prevent their delivery to lysosomes; and (d) the expression of members of the host-induced repetitive glycine-rich protein family of proteins. However, the mechanisms by which M. tuberculosis H(37)Rv enters the host cell, circumvents host defenses and spreads to neighboring cell are not completely understood. Therefore, a better understanding of host-pathogen interaction is essential if the global tuberculosis pandemic is ever to be controlled. This review addresses some of the pathogenic strategies of the M. tuberculosis H(37)Rv that aids in its survival and pathogenicity.
Topics: Bacterial Proteins; Cell Survival; Gene Expression Regulation, Bacterial; Host-Pathogen Interactions; Humans; Lysosomes; Macrophages; Mycobacterium tuberculosis; Phagocytosis; Phagosomes; Receptors, Cell Surface; Tuberculosis; Virulence
PubMed: 20553485
DOI: 10.1111/j.1742-4658.2010.07666.x -
Traffic (Copenhagen, Denmark) Oct 2013Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved intracellular catabolic transport route that generally allows the lysosomal... (Review)
Review
Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved intracellular catabolic transport route that generally allows the lysosomal degradation of cytoplasmic components, including bulk cytosol, protein aggregates, damaged or superfluous organelles and invading microbes. Target structures are sequestered by double-membrane vesicles called autophagosomes, which are formed through the concerted action of the autophagy (ATG)-related proteins. Until recently it was assumed that ATG proteins were exclusively involved in autophagy. A growing number of studies, however, have attributed functions to some of them that are distinct from their classical role in autophagosome biogenesis. Autophagy-independent roles of the ATG proteins include the maintenance of cellular homeostasis and resistance to pathogens. For example, they assist and enhance the turnover of dead cells and microbes upon their phagocytic engulfment, and inhibit murine norovirus replication. Moreover, bone resorption by osteoclasts, innate immune regulation triggered by cytoplasmic DNA and the ER-associated degradation regulation all have in common the requirement of a subset of ATG proteins. Microorganisms such as coronaviruses, Chlamydia trachomatis or Brucella abortus have even evolved ways to manipulate autophagy-independent functions of ATG proteins in order to ensure the completion of their intracellular life cycle. Taken together these novel mechanisms add to the repertoire of functions and extend the number of cellular processes involving the ATG proteins.
Topics: Animals; Autophagy; Homeostasis; Humans; Phagosomes; Proteins
PubMed: 23837619
DOI: 10.1111/tra.12091 -
Nature Reviews. Molecular Cell Biology Aug 2008The ingestion of particles or cells by phagocytosis and of fluids by macropinocytosis requires the formation of large endocytic vacuolar compartments inside cells by the... (Review)
Review
The ingestion of particles or cells by phagocytosis and of fluids by macropinocytosis requires the formation of large endocytic vacuolar compartments inside cells by the organized movements of membranes and the actin cytoskeleton. Fc-receptor-mediated phagocytosis is guided by the zipper-like progression of local, receptor-initiated responses that conform to particle geometry. By contrast, macropinosomes and some phagosomes form with little or no guidance from receptors. The common organizing structure is a cup-shaped invagination of the plasma membrane that becomes the phagosome or macropinosome. Recent studies, focusing on the physical properties of forming cups, indicate that a feedback mechanism regulates the signal transduction of phagocytosis and macropinocytosis.
Topics: Animals; Cell Physiological Phenomena; Cell Shape; Feedback, Physiological; Humans; Models, Biological; Phagocytosis; Phagosomes; Pinocytosis; Signal Transduction
PubMed: 18612320
DOI: 10.1038/nrm2447 -
Autophagy May 2016The macroautophagy (hereafter autophagy) process involves de novo formation of double-membrane autophagosomes; after sequestering cytoplasm these transient organelles... (Review)
Review
The macroautophagy (hereafter autophagy) process involves de novo formation of double-membrane autophagosomes; after sequestering cytoplasm these transient organelles fuse with the vacuole/lysosome. Genetic studies in yeasts have characterized more than 40 autophagy-related (Atg) proteins required for autophagy, and the majority of these proteins play roles in autophagosome formation. The fusion of autophagosomes with the vacuole is mediated by the Rab GTPase Ypt7, its guanine nucleotide exchange factor Mon1-Ccz1, and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. However, these factors are not autophagosome-vacuole fusion specific. We recently showed that 2 autophagy scaffold proteins, the Atg17-Atg31-Atg29 complex and Atg11, regulate autophagosome-vacuole fusion by recruiting the vacuolar SNARE Vam7 to the phagophore assembly site (PAS), where an autophagosome forms in yeast.
Topics: Animals; Autophagosomes; Autophagy; Autophagy-Related Proteins; Carrier Proteins; Humans; Phagosomes; Vacuoles
PubMed: 26986547
DOI: 10.1080/15548627.2016.1162364 -
Cell Death and Differentiation Mar 2019Autophagy is a conserved intracellular degradation pathway essential for protein homeostasis, survival and development. Defects in autophagic pathways have been... (Review)
Review
Autophagy is a conserved intracellular degradation pathway essential for protein homeostasis, survival and development. Defects in autophagic pathways have been connected to a variety of human diseases, including cancer and neurodegeneration. In the process of macroautophagy, cytoplasmic cargo is enclosed in a double-membrane structure and fused to the lysosome to allow for digestion and recycling of material. Autophagosome formation is primed by the ULK complex, which enables the downstream production of PI(3)P, a key lipid signalling molecule, on the phagophore membrane. The PI(3)P is generated by the PI3 kinase (PI3K) complex, consisting of the core components VPS34, VPS15 and Beclin 1. Beclin 1 is a central player in autophagy and constitutes a molecular platform for the regulation of autophagosome formation and maturation. Post-translational modifications of Beclin 1 affect its stability, interactions and ability to regulate PI3K activity, providing the cell with a plethora of strategies to fine-tune the levels of autophagy. Being such an important regulator, Beclin 1 is a potential target for therapeutic intervention and interfering with the post-translational regulation of Beclin 1 could be one way of manipulating the levels of autophagy. In this review, we provide an overview of the known post-translational modifications of Beclin 1 that govern its role in autophagy and how these modifications are maintained by input from several upstream signalling pathways. ▓.
Topics: Animals; Autophagy; Autophagy-Related Proteins; Beclin-1; Class III Phosphatidylinositol 3-Kinases; Humans; Phagosomes; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Phosphorylation; Protein Processing, Post-Translational; Signal Transduction; Ubiquitination
PubMed: 30546075
DOI: 10.1038/s41418-018-0254-9 -
The FEBS Journal Nov 2020Autophagosomes are vital organelles required to facilitate the lysosomal degradation of cytoplasmic cargo, thereby playing an important role in maintaining cellular... (Review)
Review
Autophagosomes are vital organelles required to facilitate the lysosomal degradation of cytoplasmic cargo, thereby playing an important role in maintaining cellular homeostasis. A number of autophagy-related (ATG) protein complexes are recruited to the site of autophagosome biogenesis where they act to facilitate membrane growth and maturation. Regulated recruitment of ATG complexes to autophagosomal membranes is essential for their autophagic activities and is required to ensure the efficient engulfment of cargo destined for lysosomal degradation. In this review, we discuss our current understanding of the spatiotemporal hierarchy between ATG proteins, examining the mechanisms underlying their recruitment to membranes. A particular focus is placed on the relevance of phosphatidylinositol 3-phosphate and the extent to which the core autophagy players are reliant on this lipid for their localisation to autophagic membranes. In addition, open questions and potential future research directions regarding the membrane recruitment and displacement of ATG proteins are discussed here.
Topics: Animals; Autophagosomes; Autophagy; Autophagy-Related Proteins; Humans; Intracellular Membranes; Lysosomes; Phagosomes; Phosphatidylinositol Phosphates; Protein Binding
PubMed: 32301577
DOI: 10.1111/febs.15334 -
FEBS Letters Aug 2014Autophagy as a conserved degradation and recycling process in eukaryotic cells, occurs constitutively, but is induced by stress. A fine regulation of autophagy in space,... (Review)
Review
Autophagy as a conserved degradation and recycling process in eukaryotic cells, occurs constitutively, but is induced by stress. A fine regulation of autophagy in space, time, and intensity is critical for maintaining normal energy homeostasis and metabolism, and to allow for its therapeutic modulation in various autophagy-related human diseases. Autophagy activity is regulated in both transcriptional and post-translational manners. In this review, we summarize the cytosolic regulation of autophagy via its molecular machinery, and nuclear regulation by transcription factors. Specifically, we consider Ume6-ATG8 and Pho23-ATG9 transcriptional regulation in detail, as examples of how nuclear transcription factors and cytosolic machinery cooperate to determine autophagosome size and number, which are the two main mechanistic factors through which autophagy activity is regulated.
Topics: Animals; Autophagy; Humans; Phagosomes; Signal Transduction; Transcription, Genetic
PubMed: 24928445
DOI: 10.1016/j.febslet.2014.06.015