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Frontiers in Immunology 2021Following phagocytosis, the nascent phagosome undergoes maturation to become a phagolysosome with an acidic, hydrolytic, and often oxidative lumen that can efficiently... (Review)
Review
Following phagocytosis, the nascent phagosome undergoes maturation to become a phagolysosome with an acidic, hydrolytic, and often oxidative lumen that can efficiently kill and digest engulfed microbes, cells, and debris. The fusion of phagosomes with lysosomes is a principal driver of phagosomal maturation and is targeted by several adapted intracellular pathogens. Impairment of this process has significant consequences for microbial infection, tissue inflammation, the onset of adaptive immunity, and disease. Given the importance of phagosome-lysosome fusion to phagocyte function and the many virulence factors that target it, it is unsurprising that multiple molecular pathways have evolved to mediate this essential process. While the full range of these pathways has yet to be fully characterized, several pathways involving proteins such as members of the Rab GTPases, tethering factors and SNAREs have been identified. Here, we summarize the current state of knowledge to clarify the ambiguities in the field and construct a more comprehensive phagolysosome formation model. Lastly, we discuss how other cellular pathways help support phagolysosome biogenesis and, consequently, phagocyte function.
Topics: Animals; Autophagy; Humans; Lysosomes; Membrane Fusion; Phagocytes; Phagocytosis; Phagosomes; SNARE Proteins; rab GTP-Binding Proteins
PubMed: 33717183
DOI: 10.3389/fimmu.2021.636078 -
Physiological Reviews Jul 2018The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein family is of vital importance for organelle communication. The complexing of... (Review)
Review
The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein family is of vital importance for organelle communication. The complexing of cognate SNARE members present in both the donor and target organellar membranes drives the membrane fusion required for intracellular transport. In the endocytic route, SNARE proteins mediate trafficking between endosomes and phagosomes with other endosomes, lysosomes, the Golgi apparatus, the plasma membrane, and the endoplasmic reticulum. The goal of this review is to provide an overview of the SNAREs involved in endosomal and phagosomal trafficking. Of the 38 SNAREs present in humans, 30 have been identified at endosomes and/or phagosomes. Many of these SNAREs are targeted by viruses and intracellular pathogens, which thereby reroute intracellular transport for gaining access to nutrients, preventing their degradation, and avoiding their detection by the immune system. A fascinating picture is emerging of a complex transport network with multiple SNAREs being involved in consecutive trafficking routes.
Topics: Animals; Endosomes; Humans; Phagosomes; SNARE Proteins
PubMed: 29790818
DOI: 10.1152/physrev.00037.2017 -
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 -
Frontiers in Immunology 2022Non-tuberculous mycobacteria (NTM) are a heterogeneous group of originally environmental organi3sms, increasingly recognized as pathogens with rising prevalence... (Review)
Review
Non-tuberculous mycobacteria (NTM) are a heterogeneous group of originally environmental organi3sms, increasingly recognized as pathogens with rising prevalence worldwide. Knowledge of NTM's mechanisms of virulence is lacking, as molecular research of these bacteria is challenging, sometimes more than that of M. tuberculosis (Mtb), and far less resources are allocated to their investigation. While some of the virulence mechanisms are common to several mycobacteria including Mtb, others NTM species-specific. Among NTMs, Mycobacterium abscessus (Mabs) causes some of the most severe and difficult to treat infections, especially chronic pulmonary infections. Mabs survives and proliferates intracellularly by circumventing host defenses, using multiple mechanisms, many of which remain poorly characterized. Some of these immune-evasion mechanisms are also found in Mtb, including phagosome pore formation, inhibition of phagosome maturation, cytokine response interference and apoptosis delay. While much is known of the role of Mtb-secreted effector molecules in mediating the manipulation of the host response, far less is known of the secreted effector molecules in Mabs. In this review, we briefly summarize the knowledge of secreted effectors in Mtb (such as ESX secretion, SecA2, TAT and others), and draw the parallel pathways in Mabs. We also describe pathways that are unique to Mabs, differentiating it from Mtb. This review will assist researchers interested in virulence-associated secretion in Mabs by providing the knowledge base and framework for their studies.
Topics: Mycobacterium abscessus; Mycobacterium tuberculosis; Nontuberculous Mycobacteria; Phagosomes; Virulence
PubMed: 35880173
DOI: 10.3389/fimmu.2022.938895 -
The FEBS Journal Mar 2021Phagocytosis is an essential mechanism for immunity and homeostasis, performed by a subset of cells known as phagocytes. Upon target engulfment, de novo formation of... (Review)
Review
Phagocytosis is an essential mechanism for immunity and homeostasis, performed by a subset of cells known as phagocytes. Upon target engulfment, de novo formation of specialized compartments termed phagosomes takes place. Phagosomes then undergo a series of fusion and fission events as they interact with the endolysosomal system and other organelles, in a dynamic process known as phagosome maturation. Because phagocytes play a key role in tissue patrolling and immune surveillance, phagosome maturation is associated with signaling pathways that link phagocytosis to antigen presentation and the development of adaptive immune responses. In addition, and depending on the nature of the cargo, phagosome integrity may be compromised, triggering additional cellular mechanisms including inflammation and autophagy. Upon completion of maturation, phagosomes enter a recently described phase: phagosome resolution, where catabolites from degraded cargo are metabolized, phagosomes are resorbed, and vesicles of phagosomal origin are recycled. Finally, phagocytes return to homeostasis and become ready for a new round of phagocytosis. Altogether, phagosome maturation and resolution encompass a series of dynamic events and organelle crosstalk that can be measured by biochemical, imaging, photoluminescence, cytometric, and immune-based assays that will be described in this guide.
Topics: Adaptive Immunity; Animals; Antigen Presentation; Autophagy; Endosomes; Humans; Immunity, Innate; Immunoassay; Immunologic Surveillance; Inflammation; Lysosomes; Molecular Probe Techniques; Phagocytes; Phagocytosis; Phagosomes; Signal Transduction
PubMed: 32757358
DOI: 10.1111/febs.15506 -
The FEBS Journal Apr 2018Rubicon (Rubcn) was initially identified as a component of the Class III PI3K complex and a negative regulator of canonical autophagy and endosomal trafficking. However,... (Review)
Review
Rubicon (Rubcn) was initially identified as a component of the Class III PI3K complex and a negative regulator of canonical autophagy and endosomal trafficking. However, Rubicon has attracted the most notoriety because of its critical role in LC3-associated phagocytosis (LAP), a form of noncanonical autophagy that utilizes some components of the autophagy machinery to process extracellular cargo. Additionally, Rubicon has been identified as a key modulator of the inflammatory response and viral replication. In this review, we discuss the known functions of Rubicon in LAP and other signaling pathways and examine the disease pathologies associated with Rubicon dysfunction in animal models and humans.
Topics: Animals; Autophagy; Autophagy-Related Proteins; Endosomes; Humans; Intracellular Signaling Peptides and Proteins; Microtubule-Associated Proteins; Models, Biological; Phagocytosis; Phagosomes; Signal Transduction
PubMed: 29215797
DOI: 10.1111/febs.14354 -
Cellular and Molecular Life Sciences :... Jul 2023During phagocytosis, endosomes both contribute with membrane to forming phagosomes and promote phagosome maturation. However, how these vesicles are delivered to the...
During phagocytosis, endosomes both contribute with membrane to forming phagosomes and promote phagosome maturation. However, how these vesicles are delivered to the phagocytic cup and the phagosome has been unknown. Here, we show that Protrudin-mediated endoplasmic reticulum (ER)-endosome contact sites facilitate anterograde translocation of FYCO1 and VAMP7-positive late endosomes and lysosomes (LELys) to forming phagocytic cups in a retinal pigment epithelial-derived cell line (RPE1). Protrudin-dependent phagocytic cup formation required SYT7, which promotes fusion of LELys with the plasma membrane. RPE1 cells perform phagocytosis of dead cells (efferocytosis) that expose phosphatidylserine (PS) on their surface. Exogenous addition of apoptotic bodies increased the formation of phagocytic cups, which further increased when Protrudin was overexpressed. Overexpression of Protrudin also led to elevated uptake of silica beads coated with PS. Conversely, Protrudin depletion or abrogation of ER-endosome contact sites inhibited phagocytic cup formation resulting in reduced uptake of PS-coated beads. Thus, the Protrudin pathway delivers endosomes to facilitate formation of the phagocytic cup important for PS-dependent phagocytosis.
Topics: Phagocytosis; Endoplasmic Reticulum; Lysosomes; Phagosomes; Endosomes
PubMed: 37468729
DOI: 10.1007/s00018-023-04862-0 -
The International Journal of... 2019The formation and processing of vesicles from the cell surface serves many important cellular functions ranging from nutrient acquisition to regulating the turnover of... (Review)
Review
The formation and processing of vesicles from the cell surface serves many important cellular functions ranging from nutrient acquisition to regulating the turnover of membrane components and signalling. In this article, we summarise the endocytic pathways of the social amoeba Dictyostelium from the clathrin-dependent and independent internalisation of surface components to the engulfment of bacteria or fluid by phagocytosis and macropinocytosis respectively. Due to similarities with the professional phagocytes of the mammalian immune system Dictyostelium has been extensively used to investigate the complex remodelling and trafficking events that occur as phagosomes and macropinosomes transit through the cell. Here we discuss what is known about this maturation process in order to kill any potential pathogens and obtain nutrients for growth. Finally, we aim to put these studies in evolutionary context and highlight some of the many questions that remain in our understanding of these complex and important pathways.
Topics: Cell Membrane; Cell Movement; Clathrin; Dictyostelium; Endocytosis; Exocytosis; Immune System; Lysosomes; Phagocytosis; Phagosomes; Pinocytosis; Signal Transduction
PubMed: 31840784
DOI: 10.1387/ijdb.190236jk -
Cellular Physiology and Biochemistry :... 2019Acid sphingomyelinase hydrolyzes sphingomyelin to ceramide and phosphorylcholine. Ceramide molecules spontaneously interact with each other and generate... (Review)
Review
Acid sphingomyelinase hydrolyzes sphingomyelin to ceramide and phosphorylcholine. Ceramide molecules spontaneously interact with each other and generate ceramide-enriched membrane domains. These ceramide-enriched domains further fuse, forming large ceramideenriched platforms that participate in the organization of receptors and in the amplification of signaling molecules. Recent studies have suggested several bacteria and bacterial toxins that stimulate the activation and the translocation of acid sphingomyelinase, which leads to the release of ceramide. The acid sphingomyelinase/ceramide system also regulates the internalization of bacteria into the host cell, the subsequent cytokine release, inflammatory response, and initiation of host cell apoptosis. In addition, ceramide has been implicated in the fusion of phagosomes and lysosomes upon bacterial infection. Thus, this system modulates the reorganization of cell membrane receptors and intracellular signaling molecules during bacteria-host interactions. The acid sphingomyelinase and ceramide system may thus serve as a novel therapeutic target for treating infections.
Topics: Animals; Bacterial Infections; Bacterial Toxins; Ceramides; Enzyme Activation; Humans; Inflammation; Lysosomes; Phagosomes; Signal Transduction; Sphingomyelin Phosphodiesterase
PubMed: 30816675
DOI: 10.33594/000000021 -
BioMed Research International 2017One hundred years have passed since the death of Élie Metchnikoff (1845-1916). He was the first to observe the uptake of particles by cells and realized the importance... (Review)
Review
One hundred years have passed since the death of Élie Metchnikoff (1845-1916). He was the first to observe the uptake of particles by cells and realized the importance of this process for the host response to injury and infection. He also was a strong advocate of the role of phagocytosis in cellular immunity, and with this he gave us the basis for our modern understanding of inflammation and the innate and acquired immune responses. Phagocytosis is an elegant but complex process for the ingestion and elimination of pathogens, but it is also important for the elimination of apoptotic cells and hence fundamental for tissue homeostasis. Phagocytosis can be divided into four main steps: (i) recognition of the target particle, (ii) signaling to activate the internalization machinery, (iii) phagosome formation, and (iv) phagolysosome maturation. In recent years, the use of new tools of molecular biology and microscopy has provided new insights into the cellular mechanisms of phagocytosis. In this review, we present a general view of our current knowledge on phagocytosis. We emphasize novel molecular findings, particularly on phagosome formation and maturation, and discuss aspects that remain incompletely understood.
Topics: Animals; Antigens; Humans; Phagocytosis; Phagosomes; Receptors, Immunologic; Signal Transduction
PubMed: 28691037
DOI: 10.1155/2017/9042851