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Biomedical Journal Jun 2017The present review summarizes recent experimental evidences about the existence of the non-cell-autonomous death entosis in physiological and pathophysiological... (Review)
Review
The present review summarizes recent experimental evidences about the existence of the non-cell-autonomous death entosis in physiological and pathophysiological contexts, discusses some aspects of this form of cell death, including morphological, biochemical and signaling pathways that distinguish non-cell-autonomous demises from other death modalities and propose to define this new modality of death as type IV programmed cell death.
Topics: Apoptosis; Autophagosomes; Autophagy; Entosis; Humans; Phagosomes; Signal Transduction
PubMed: 28651734
DOI: 10.1016/j.bj.2017.05.001 -
Autophagy Feb 2008Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of... (Review)
Review
Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
Topics: Animals; Autophagy; Autophagy-Related Protein 8 Family; Clinical Laboratory Techniques; Data Interpretation, Statistical; Eukaryotic Cells; Guidelines as Topic; Humans; Microscopy, Fluorescence; Microtubule-Associated Proteins; Models, Biological; Phagosomes; Plants; Protein Processing, Post-Translational; Protein Transport; Saccharomyces cerevisiae Proteins
PubMed: 18188003
DOI: 10.4161/auto.5338 -
FEBS Letters Apr 2010Autophagosomes (APs) are unique organelles that enwrap cytoplasmic components when necessary. APs then fuse with lysosomes and enclosed materials are degraded. Although... (Review)
Review
Autophagosomes (APs) are unique organelles that enwrap cytoplasmic components when necessary. APs then fuse with lysosomes and enclosed materials are degraded. Although approximately 30 autophagy-related genes (ATG) required for AP formation have been identified, fundamental questions on the membrane source or dynamics during the formation remain unresolved. Here, we present a comprehensive overview of the putative membrane sources identified to date.
Topics: Animals; Autophagy; Cell Membrane; Endoplasmic Reticulum; Golgi Apparatus; Membrane Proteins; Phagosomes
PubMed: 20188731
DOI: 10.1016/j.febslet.2010.02.061 -
Laboratory Investigation; a Journal of... Nov 2021The mortality rates among patients who initially survive sepsis are, in part, associated with a high risk of secondary lung infections and respiratory failure. Given...
The mortality rates among patients who initially survive sepsis are, in part, associated with a high risk of secondary lung infections and respiratory failure. Given that phagolysosomes are important for intracellular killing of pathogenic microbes, we investigated how severe lung infections associated with post-sepsis immunosuppression affect phagolysosome biogenesis. In mice with P. aeruginosa-induced pneumonia, we found a depletion of both phagosomes and lysosomes, as evidenced by decreased amounts of microtubule associated protein light chain 3-II (LC3-II) and lysosomal-associated membrane protein (LAMP1). We also found a loss of transcription factor E3 (TFE3) and transcription factor EB (TFEB), which are important activators for transcription of genes encoding autophagy and lysosomal proteins. These events were associated with increased expression of ZKSCAN3, a repressor for transcription of genes encoding autophagy and lysosomal proteins. Zkscan3 mice had increased expression of genes involved in the autophagy-lysosomal pathway along with enhanced killing of P. aeruginosa in the lungs, as compared to wild-type mice. These findings highlight the involvement of ZKSCAN3 in response to severe lung infection, including susceptibility to secondary bacterial infections due to immunosuppression.
Topics: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Immune Tolerance; Lung; Male; Mice, Inbred C57BL; Phagosomes; Pneumonia, Bacterial; Pseudomonas Infections; Pseudomonas aeruginosa; Sepsis; Transcription Factors; Mice
PubMed: 34504306
DOI: 10.1038/s41374-021-00660-z -
Nature Reviews. Molecular Cell Biology Oct 2008Phagosome maturation is the process by which internalized particles (such as bacteria and apoptotic cells) are trafficked into a series of increasingly acidified... (Review)
Review
Phagosome maturation is the process by which internalized particles (such as bacteria and apoptotic cells) are trafficked into a series of increasingly acidified membrane-bound structures, leading to particle degradation. The characterization of the phagosomal proteome and studies in model organisms and mammals have led to the identification of numerous candidate proteins that cooperate to control the maturation of phagosomes containing different particles. A subset of these candidate proteins makes up the first pathway to be identified for the maturation of apoptotic cell-containing phagosomes. This suggests that a machinery that is distinct from receptor-mediated endocytosis is used in phagosome maturation.
Topics: Animals; Apoptosis; Endocytosis; Humans; Models, Biological; Phagocytes; Phagocytosis; Phagosomes; Proteomics; Signal Transduction; Toll-Like Receptors; Vacuolar Proton-Translocating ATPases; rab GTP-Binding Proteins
PubMed: 18813294
DOI: 10.1038/nrm2515 -
Cell Host & Microbe Aug 2009Shigella flexneri and other invasive bacteria rupture the phagosome membrane and escape to the host cytoplasm. Now, Dupont et al. address the fate and signaling... (Review)
Review
Shigella flexneri and other invasive bacteria rupture the phagosome membrane and escape to the host cytoplasm. Now, Dupont et al. address the fate and signaling functions of pathogen vacuole remnants and show that these membrane fragments trigger host-cell-signaling responses, including polyubiquitination, autophagy, and pyroptosis.
Topics: Autophagy; Cell Membrane; Models, Biological; Phagosomes; Shigella flexneri; Signal Transduction; Ubiquitination
PubMed: 19683675
DOI: 10.1016/j.chom.2009.08.001 -
Communications Biology Sep 2022Immune cells degrade internalized pathogens in phagosomes through sequential biochemical changes. The degradation must be fast enough for effective infection control....
Immune cells degrade internalized pathogens in phagosomes through sequential biochemical changes. The degradation must be fast enough for effective infection control. The presumption is that each phagosome degrades cargos autonomously with a distinct but stochastic kinetic rate. However, here we show that the degradation kinetics of individual phagosomes is not stochastic but coupled to their intracellular motility. By engineering RotSensors that are optically anisotropic, magnetic responsive, and fluorogenic in response to degradation activities in phagosomes, we monitored cargo degradation kinetics in single phagosomes simultaneously with their translational and rotational dynamics. We show that phagosomes that move faster centripetally are more likely to encounter and fuse with lysosomes, thereby acidifying faster and degrading cargos more efficiently. The degradation rates increase nearly linearly with the translational and rotational velocities of phagosomes. Our results indicate that the centripetal motion of phagosomes functions as a clock for controlling the progression of cargo degradation.
Topics: Cell Movement; Kinetics; Lysosomes; Phagocytosis; Phagosomes
PubMed: 36163370
DOI: 10.1038/s42003-022-03988-4 -
Biochimica Et Biophysica Acta Sep 2009Autophagy is a tightly regulated cell self-eating process. It has been shown to be associated with various neuropathological conditions and therefore, traditionally... (Review)
Review
Autophagy is a tightly regulated cell self-eating process. It has been shown to be associated with various neuropathological conditions and therefore, traditionally known as a stress-induced process. Recent studies, however, reveal that autophagy is constitutively active in healthy neurons. Neurons are highly specialized, post-mitotic cells that are typically composed of a soma (cell body), a dendritic tree, and an axon. Despite the vast growth of our current knowledge of autophagy, the detailed process in such a highly differentiated cell type remains elusive. Current evidence strongly suggests that autophagy is uniquely regulated in neurons and is also highly adapted to local physiology in the axons. In addition, the molecular mechanism for basal autophagy in neurons may be significantly divergent from "classical" induced autophagy. A considerable number of studies have increasingly shown an important role for autophagy in neurodegenerative diseases and have explored autophagy as a potential drug target. Thus, understanding the neuronal autophagy process will ultimately aid in drug target identification and rational design of drug screening to combat neurodegenerative diseases.
Topics: Animals; Autophagy; Disease; Humans; Neurodegenerative Diseases; Neurons; Phagosomes; Signal Transduction
PubMed: 19339210
DOI: 10.1016/j.bbamcr.2009.01.016 -
The Journal of Biological Chemistry Mar 2018is a Gram-negative zoonotic pathogen for which there is no 100% effective vaccine. Phagosomes in -infected cells fail to mature, allowing the pathogen to survive and...
is a Gram-negative zoonotic pathogen for which there is no 100% effective vaccine. Phagosomes in -infected cells fail to mature, allowing the pathogen to survive and proliferate. Interleukin 10 (IL10) promotes persistence in macrophages by mechanisms that are not fully understood. In this study, we investigated the regulatory role of IL10 in the immune response to infection. -infected macrophages were treated with either IL10 siRNA or recombinant IL10 (rIL10), and the expression of phagolysosome- or inflammation-related genes was evaluated by qRT-PCR and Western blotting. Phagolysosome fusion was monitored by fluorescence microscopy. We found that the synthesis of several membrane-trafficking regulators and lysosomal enzymes was suppressed by IL10 during infection, resulting in a significant increase in the recruitment of hydrolytic enzymes by -containing phagosomes (BCPs) when IL10 signaling was blocked. Moreover, blocking IL10 signaling also enhanced proinflammatory cytokine production. Finally, concomitant treatment with STAT3 siRNA significantly reduced the suppression of proinflammatory brucellacidal activity but not phagolysosome fusion by rIL10. Thus, our data provide the first evidence that clearly indicates the suppressive role of IL10 on phagolysosome fusion and inflammation in response to infection through two distinct mechanisms, STAT3-independent and -dependent pathways, respectively, in murine macrophages.
Topics: Animals; Brucella abortus; Interleukin-10; Lysosomes; Macrophages; Mice; Phagosomes; RAW 264.7 Cells; STAT3 Transcription Factor; Up-Regulation
PubMed: 29301939
DOI: 10.1074/jbc.M117.805556 -
Molecular Biology of the Cell Feb 2018Phagosomes mature into phagolysosomes by sequential fusion with early endosomes, late endosomes, and lysosomes. Phagosome-with-lysosome fusion (PLF) results in the...
Phagosomes mature into phagolysosomes by sequential fusion with early endosomes, late endosomes, and lysosomes. Phagosome-with-lysosome fusion (PLF) results in the delivery of lysosomal hydrolases into phagosomes and in digestion of the cargo. The machinery that drives PLF has been little investigated. Using a cell-free system, we recently identified the phosphoinositide lipids (PIPs) phosphatidylinositol 3-phosphate (PI(3)P) and phosphatidylinositol 4-phosphate (PI(4)P) as regulators of PLF. We now report the identification and the PIP requirements of four distinct subreactions of PLF. Our data show that (i) PI(3)P and PI(4)P are dispensable for the disassembly and activation of (phago)lysosomal soluble -ethylmaleimide-sensitive factor attachment protein receptors, that (ii) PI(3)P is required only after the tethering step, and that (iii) PI(4)P is required during and after tethering. Moreover, our data indicate that PI(4)P is needed to anchor Arl8 (Arf-like GTPase 8) and its effector homotypic fusion/vacuole protein sorting complex (HOPS) to (phago)lysosome membranes, whereas PI(3)P is required for membrane association of HOPS only. Our study provides a first link between PIPs and established regulators of membrane fusion in late endocytic trafficking.
Topics: Animals; Cell Line; Cell-Free System; Endosomes; Intracellular Membranes; Lysosomes; Mice; Phagocytosis; Phagosomes; Phosphatidylinositol Phosphates; Protein Transport; SNARE Proteins
PubMed: 29237821
DOI: 10.1091/mbc.E17-07-0464