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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 -
PLoS Pathogens Mar 2023Macrophages are a first line of defense against pathogens. However, certain invading microbes modify macrophage responses to promote their own survival and growth....
Activation of transcription factor CREB in human macrophages by Mycobacterium tuberculosis promotes bacterial survival, reduces NF-kB nuclear transit and limits phagolysosome fusion by reduced necroptotic signaling.
Macrophages are a first line of defense against pathogens. However, certain invading microbes modify macrophage responses to promote their own survival and growth. Mycobacterium tuberculosis (M.tb) is a human-adapted intracellular pathogen that exploits macrophages as an intracellular niche. It was previously reported that M.tb rapidly activates cAMP Response Element Binding Protein (CREB), a transcription factor that regulates diverse cellular responses in macrophages. However, the mechanism(s) underlying CREB activation and its downstream roles in human macrophage responses to M.tb are largely unknown. Herein we determined that M.tb-induced CREB activation is dependent on signaling through MAPK p38 in human monocyte-derived macrophages (MDMs). Using a CREB-specific inhibitor, we determined that M.tb-induced CREB activation leads to expression of immediate early genes including COX2, MCL-1, CCL8 and c-FOS, as well as inhibition of NF-kB p65 nuclear localization. These early CREB-mediated signaling events predicted that CREB inhibition would lead to enhanced macrophage control of M.tb growth, which we observed over days in culture. CREB inhibition also led to phosphorylation of RIPK3 and MLKL, hallmarks of necroptosis. However, this was unaccompanied by cell death at the time points tested. Instead, bacterial control corresponded with increased colocalization of M.tb with the late endosome/lysosome marker LAMP-1. Increased phagolysosomal fusion detected during CREB inhibition was dependent on RIPK3-induced pMLKL, indicating that M.tb-induced CREB signaling limits phagolysosomal fusion through inhibition of the necroptotic signaling pathway. Altogether, our data show that M.tb induces CREB activation in human macrophages early post-infection to create an environment conducive to bacterial growth. Targeting certain aspects of the CREB-induced signaling pathway may represent an innovative approach for development of host-directed therapeutics to combat TB.
Topics: Humans; Cyclic AMP Response Element-Binding Protein; Macrophages; Mycobacterium tuberculosis; Necroptosis; NF-kappa B; Phagosomes; Signal Transduction; Tuberculosis
PubMed: 37000865
DOI: 10.1371/journal.ppat.1011297 -
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 -
Frontiers in Cellular and Infection... 2021Cells of the innate immune system continuously patrol the extracellular environment for potential microbial threats that are to be neutralized by phagocytosis and... (Review)
Review
Cells of the innate immune system continuously patrol the extracellular environment for potential microbial threats that are to be neutralized by phagocytosis and delivery to lysosomes. In addition, phagocytes employ autophagy as an innate immune mechanism against pathogens that succeed to escape the phagolysosomal pathway and invade the cytosol. In recent years, LC3-associated phagocytosis (LAP) has emerged as an intermediate between phagocytosis and autophagy. During LAP, phagocytes target extracellular microbes while using parts of the autophagic machinery to label the cargo-containing phagosomes for lysosomal degradation. LAP contributes greatly to host immunity against a multitude of bacterial pathogens. In the pursuit of survival, bacteria have developed elaborate strategies to disarm or circumvent the LAP process. In this review, we will outline the nature of the LAP mechanism and discuss recent insights into its interplay with bacterial pathogens.
Topics: Autophagy; Bacteria; Microtubule-Associated Proteins; Phagocytosis; Phagosomes
PubMed: 35047422
DOI: 10.3389/fcimb.2021.809121 -
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 -
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 -
Glycobiology Sep 2013A growing list of innate immune receptors is being defined that recognize polysaccharides of microbial cell walls. Fungal β-glucan recognition by the receptor Dectin-1... (Review)
Review
A growing list of innate immune receptors is being defined that recognize polysaccharides of microbial cell walls. Fungal β-glucan recognition by the receptor Dectin-1 triggers inflammatory immune responses in macrophages and dendritic cells that are appropriate for defense against fungal pathogens. Among these responses is the specific recruitment of the autophagy-related protein light chain 3 (LC3) to phagosomes containing fungi. Studies documenting LC3's recruitment to phagosomes containing β-glucan and other nonsugar particles suggest that LC3 plays a role in regulating phagocytosis and its related immunological responses.
Topics: Animals; Autophagy; Humans; Lectins, C-Type; Phagocytosis; Phagosomes; Signal Transduction; beta-Glucans
PubMed: 23749474
DOI: 10.1093/glycob/cwt046 -
Autophagy Feb 2021Macroautophagy/autophagy is a complex process that involves over 40 proteins in . How these proteins are organized, and their activities orchestrated to facilitate an...
Macroautophagy/autophagy is a complex process that involves over 40 proteins in . How these proteins are organized, and their activities orchestrated to facilitate an efficient autophagic mechanism remain elusive. Sawa-Makarsha et al. reconstitute the initial steps of autophagosome biogenesis during selective autophagy using autophagy factors purified from yeast. Their results show that Atg9 vesicles serve as platforms for the recruitment of the autophagy machinery, and establish membrane contact sites to initiate lipid transfer for autophagosome biogenesis.: GUV, giant unilamellar vesicles; PAS, phagophore assembly site; PL, proteolipisomes.
Topics: Autophagosomes; Autophagy; Autophagy-Related Proteins; Membrane Proteins; Phagosomes; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 33092448
DOI: 10.1080/15548627.2020.1835231 -
Journal of Neuroimmunology Jul 2013Within the immunosuppressive ocular microenvironment, there are constitutively present the immunomodulating neuropeptides alpha-melanocyte stimulating hormone (α-MSH)...
Within the immunosuppressive ocular microenvironment, there are constitutively present the immunomodulating neuropeptides alpha-melanocyte stimulating hormone (α-MSH) and neuropeptide Y (NPY) that promote suppressor functionality in macrophages. In this study, we examined the possibility that α-MSH and NPY modulate phagocytic activity in macrophages. The macrophages treated with α-MSH and NPY were significantly suppressed in their capacity to phagocytize unopsonized Escherichia coli and Staphylococcus aureus bioparticles, but not antibody-opsonized bioparticles. The neuropeptides significantly suppressed phagolysosome activation, and the FcR-associated generation of reactive oxidative species as well. This suppression corresponds to neuropeptide modulation of macrophage functionality within the ocular microenvironment to suppress the activation of immunogenic inflammation.
Topics: Animals; Cell Line, Tumor; Escherichia coli; Escherichia coli Infections; Leukemia, Monocytic, Acute; Macrophages; Mice; Neuroimmunomodulation; Neuropeptide Y; Phagocytosis; Phagosomes; Reactive Oxygen Species; Retina; Staphylococcal Infections; Staphylococcus aureus; alpha-MSH
PubMed: 23689030
DOI: 10.1016/j.jneuroim.2013.04.019 -
Microbiology Spectrum Oct 2014Through thousands of years of reciprocal coevolution, Mycobacterium tuberculosis has become one of humanity's most successful pathogens, acquiring the ability to... (Review)
Review
Through thousands of years of reciprocal coevolution, Mycobacterium tuberculosis has become one of humanity's most successful pathogens, acquiring the ability to establish latent or progressive infection and persist even in the presence of a fully functioning immune system. The ability of M. tuberculosis to avoid immune-mediated clearance is likely to reflect a highly evolved and coordinated program of immune evasion strategies that interfere with both innate and adaptive immunity. These include the manipulation of their phagosomal environment within host macrophages, the selective avoidance or engagement of pattern recognition receptors, modulation of host cytokine production, and the manipulation of antigen presentation to prevent or alter the quality of T-cell responses. In this article we review an extensive array of published studies that have begun to unravel the sophisticated program of specific mechanisms that enable M. tuberculosis and other pathogenic mycobacteria to persist and replicate in the face of considerable immunological pressure from their hosts. Unraveling the mechanisms by which M. tuberculosis evades or modulates host immune function is likely to be of major importance for the development of more effective new vaccines and targeted immunotherapy against tuberculosis.
Topics: Adaptive Immunity; Animals; Host-Pathogen Interactions; Humans; Immune Evasion; Immunity, Innate; Macrophages; Mycobacterium tuberculosis; Phagosomes
PubMed: 26104343
DOI: 10.1128/microbiolspec.MGM2-0005-2013