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Advances in Experimental Medicine and... 2020The key purpose of phagocytosis is the destruction of pathogenic microorganisms. The phagocytes exert a wide array of killing mechanisms that allow mastering the vast... (Review)
Review
The key purpose of phagocytosis is the destruction of pathogenic microorganisms. The phagocytes exert a wide array of killing mechanisms that allow mastering the vast majority of pathogens. One of these mechanisms consists in the production of reactive oxygen species inside the phagosome by a specific enzyme, the phagocyte NADPH oxidase. This enzyme is composed of 6 proteins that need to assemble to form a complex on the phagosomal membrane. Multiple signaling pathways tightly regulate the assembly. We briefly summarize key features of the enzyme and its regulation. We then focus on several related topics that address the activity of the NADPH oxidase during phagocytosis. Novel fluorescence microscopy techniques combined with fluorescent protein labeling of NADPH oxidase subunits opened the view on the structure and dynamics of these proteins in living cells. This combination revealed details of the role of anionic phospholipids in the control of phagosomal ROS production. It also added critical information to propose a 3D model of the complex between the cytosolic subunits prior to activation, in complement to other structural data on the oxidase.
Topics: Humans; NADPH Oxidases; Phagocytes; Phagocytosis; Phagosomes; Reactive Oxygen Species
PubMed: 32399830
DOI: 10.1007/978-3-030-40406-2_9 -
Nature Reviews. Molecular Cell Biology Aug 2015Autophagy is a conserved catabolic process that degrades cytoplasmic constituents and organelles in the lysosome. Starvation-induced protein degradation is a salient... (Review)
Review
Autophagy is a conserved catabolic process that degrades cytoplasmic constituents and organelles in the lysosome. Starvation-induced protein degradation is a salient feature of autophagy but recent progress has illuminated how autophagy, during both starvation and nutrient-replete conditions, can mobilize diverse cellular energy and nutrient stores such as lipids, carbohydrates and iron. Processes such as lipophagy, glycophagy and ferritinophagy enable cells to salvage key metabolites to sustain and facilitate core anabolic functions. Here, we discuss the established and emerging roles of autophagy in fuelling biosynthetic capacity and in promoting metabolic and nutrient homeostasis.
Topics: Adipogenesis; Animals; Autophagy; Carbohydrate Metabolism; Energy Metabolism; Humans; Iron; Phagosomes; Protein Transport; Proteolysis
PubMed: 26177004
DOI: 10.1038/nrm4024 -
Immunology and Cell Biology Jan 2015Autophagy has become increasingly viewed as an important component of the eukaryotic innate immune system. The elimination of intracellular pathogens by autophagy in... (Review)
Review
Autophagy has become increasingly viewed as an important component of the eukaryotic innate immune system. The elimination of intracellular pathogens by autophagy in mammalian cells (xenophagy) results not only in the degradation of invading bacteria, viruses, fungi and parasites, but also liberation of metabolites that may have been utilized during pathogen infection, thus promoting cell survival. After gaining entry into the cell, intracellular bacterial pathogens attempt to escape from phagosomes (or endosomes) into the cytosol where they endeavour to continue the infection cycle unhindered by host cell protective mechanisms. Bacterial recognition resulting from either their cytosolic location, the secretion of bacterial products, or phagosomal membrane damage, can induce autophagy. In this context, induction of autophagy results in the clearance of some bacterial pathogens, whereas other bacteria are able to manipulate autophagy for their own benefit and appear to effectively replicate within autophagosome-like vesicles. Some bacteria are seemingly able to evade autophagy and Burkholderia pseudomallei is one of them. This review will discuss the autophagic processes that may be activated by host cells to provide protection against infection by this bacterial pathogen.
Topics: Autophagy; Bacterial Proteins; Burkholderia pseudomallei; Gene Expression Regulation; Host-Pathogen Interactions; Humans; Immune Evasion; Immunity, Innate; Macrophages; Melioidosis; Microtubule-Associated Proteins; Phagosomes; Signal Transduction; Ubiquitin
PubMed: 25331551
DOI: 10.1038/icb.2014.87 -
Immunological Reviews Mar 2023The neutrophil phagosome is one of the most hostile environments that bacteria must face and overcome if they are to succeed as pathogens. Targeting bacterial defense... (Review)
Review
The neutrophil phagosome is one of the most hostile environments that bacteria must face and overcome if they are to succeed as pathogens. Targeting bacterial defense mechanisms should lead to new therapies that assist neutrophils to kill pathogens, but this has not yet come to fruition. One of the limiting factors in this effort has been our incomplete knowledge of the complex biochemistry that occurs within the rapidly changing environment of the phagosome. The same compartmentalization that protects host tissue also limits our ability to measure events within the phagosome. In this review, we highlight the limitations in our knowledge, and how the contribution of bacteria to the phagosomal environment is often ignored. There appears to be significant heterogeneity among phagosomes, and it is important to determine whether survivors have more efficient defenses or whether they are ingested into less threatening environments than other bacteria. As part of these efforts, we discuss how monitoring or recovering bacteria from phagosomes can provide insight into the conditions they have faced. We also encourage the use of unbiased screening approaches to identify bacterial genes that are essential for survival inside neutrophil phagosomes.
Topics: Humans; Phagosomes; Neutrophils; Bacteria; Phagocytosis
PubMed: 36625601
DOI: 10.1111/imr.13182 -
International Journal of Medical... Jan 2018Phagocytosis is essential for uptake and elimination of pathogenic microorganisms. Autophagy is a highly conserved mechanism for incorporation of cellular constituents... (Review)
Review
Phagocytosis is essential for uptake and elimination of pathogenic microorganisms. Autophagy is a highly conserved mechanism for incorporation of cellular constituents to replenish nutrients by degradation. Recently, parts of the autophagy machinery - above all microtubule-associated protein 1 light chain 3 (LC3) - were found to be specifically recruited to phagosomal membranes resulting in phagosome-lysosome fusion and efficient degradation of internalized cargo in a process termed LC3-associated phagocytosis (LAP). Many pathogenic bacterial, fungal and parasitic microorganisms reside within LAP-targeted single-membrane phagosomes or vacuoles after infection of host cells. In this minireview we describe the state of knowledge on the interaction of pathogens with LAP or LAP-like pathways and report on various pathogens that have evolved strategies to circumvent degradation in LAP compartments.
Topics: Animals; Bacteria; Fungi; Humans; Immune Evasion; Microtubule-Associated Proteins; Parasites; Phagocytosis; Phagosomes; Vacuoles
PubMed: 29169848
DOI: 10.1016/j.ijmm.2017.10.014 -
Molecules and Cells Jan 2018Atg5 and Atg7 have long been considered as essential molecules for autophagy. However, we found that cells lacking these molecules still form autophagic vacuoles and... (Review)
Review
Atg5 and Atg7 have long been considered as essential molecules for autophagy. However, we found that cells lacking these molecules still form autophagic vacuoles and perform autophagic protein degradation when subjected to certain stressors. During this unconventional autophagy pathway, autophagosomes appeared to be generated in a Rab9-dependent manner by the fusion of vesicles derived from the -Golgi and late endosomes. Therefore, mammalian autophagy can occur via at least two different pathways; the Atg5/Atg7-dependent conventional pathway and an Atg5/Atg7-independent alternative pathway.
Topics: Animals; Autophagosomes; Autophagy; Autophagy-Related Protein 5; Autophagy-Related Protein 7; Humans; Lysosomes; Microtubule-Associated Proteins; Models, Biological; Phagosomes
PubMed: 29370693
DOI: 10.14348/molcells.2018.2215 -
Pathogens and Disease Oct 2022Given the emergence and spread of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb), the world faces the urgency of finding... (Review)
Review
Given the emergence and spread of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb), the world faces the urgency of finding new drugs to combat tuberculosis. Understanding the biochemical/physiological processes enabling Mtb to survive the stressful environment within macrophages and acquire tolerance, resistance and persistence against the stresses are the key to developing new approaches to tackle this health problem. As Mtb gains entry into the respiratory tract and is engulfed by macrophages, lowering pH acts as a primary defence of phagosomes within macrophages and also in the centres of caseating granulomas. It becomes essential for the pathogen to maintain pH homeostasis for survival in these conditions. Acid resistance mechanisms are well known and extensively studied in other bacteria such as Escherichia coli, Lactobacillus spp., Brucella spp., Helicobacter pylori and Listeria monocytogenes. However, in the case of Mtb, acid tolerance and resistance mechanisms still need to be explored in detail. This review aims to describe the current understanding of underlying mechanisms involved in countering low pH faced by Mtb as the acid resistance/tolerance mechanisms contribute to the pathogenesis of the disease.
Topics: Humans; Listeria monocytogenes; Macrophages; Mycobacterium tuberculosis; Phagosomes; Tuberculosis
PubMed: 35953394
DOI: 10.1093/femspd/ftac032 -
Virulence Dec 2019Autophagy is a conserved and fundamental cellular process mainly to recycle or eliminate dysfunctional cellular organelles or proteins. As a response to cellular stress,... (Review)
Review
Autophagy is a conserved and fundamental cellular process mainly to recycle or eliminate dysfunctional cellular organelles or proteins. As a response to cellular stress, autophagy is used as a defense mechanism to combat the infection with pathogenic bacteria. However, many intracellular bacteria have developed diverse mechanisms to evade recognition, to manipulate the autophagic pathway, and to hijack the autophagosomal compartment for replication. In this review, we discuss recent understandings on how bacteria interact with host autophagy.
Topics: Autophagy; Bacteria; Cytoplasm; Host-Pathogen Interactions; Humans; Lysosomes; Phagosomes
PubMed: 30978154
DOI: 10.1080/21505594.2019.1602020 -
Journal of Cell Science Apr 2015Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway,... (Review)
Review
Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway, which is particularly crucial in neurons. There is increasing evidence implicating defective autophagy in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease. Recent work using live-cell imaging has identified autophagy as a predominantly polarized process in neuronal axons; autophagosomes preferentially form at the axon tip and undergo retrograde transport back towards the cell body. Autophagosomes engulf cargo including damaged mitochondria (mitophagy) and protein aggregates, and subsequently fuse with lysosomes during axonal transport to effectively degrade their internalized cargo. In this Cell Science at a Glance article and the accompanying poster, we review recent progress on the dynamics of the autophagy pathway in neurons and highlight the defects observed at each step of this pathway during neurodegeneration.
Topics: Animals; Autophagy; Humans; Neurodegenerative Diseases; Neurons; Phagosomes
PubMed: 25829512
DOI: 10.1242/jcs.161216 -
International Reviews of Immunology 2019Phagosome-lysosome (P-L) fusion is one of the central immune-effector responses of host. It is known that phagosome maturation process is associated with numerous... (Review)
Review
Phagosome-lysosome (P-L) fusion is one of the central immune-effector responses of host. It is known that phagosome maturation process is associated with numerous signaling cascades and among these, important role of calcium (Ca) signaling has been realized recently. Ca plays key roles in actin rearrangement, activation of NADPH oxidase and protein kinase C (PKC). Involvement of Ca in these cellular processes directs phagosomal maturation process. Some of the intracellular pathogens have acquired the strategies to modulate Ca associated pathways to block P-L fusion process. In this review we have described the mechanism of Ca signals that influence P-L fusion by controlling ROS, actin and PKC signaling cascades. We have also discussed the strategies implemented by the intracellular pathogens to manipulate Ca signaling to consequently subvert P-L fusion. A detail study of factors associated in manipulating Ca signaling may provide new insights for the development of therapeutic tools for more effective treatment options against infectious diseases.
Topics: Actins; Animals; Calcium; Calcium Signaling; Cytotoxicity, Immunologic; Humans; Intracellular Space; Lysosomes; Macrophages; Phagocytosis; Phagosomes; Protein Kinase C; Reactive Oxygen Species; Signal Transduction
PubMed: 31117900
DOI: 10.1080/08830185.2019.1592169