Survival of Salmonella typhimurium within macrophage phagosomes requires the coordinate expression of bacterial gene products. This report examines the contribution of phagosomal pH as a signal for expression of genes positively regulated by the S. typhimurium virulence regulators PhoP and PhoQ. Several hours after bacterial phagocytosis by murine bone marrow-derived macrophages, PhoP-activated gene transcription increased 50- to 77-fold. In contrast, no difference in PhoP-activated gene expression was observed after infection of cultured epithelial cells, suggesting that the membrane sensor PhoQ recognized signals unique to macrophage phagosomes. The increase in PhoP-regulated gene expression was abolished when macrophage culture medium contained NH4Cl or chloroquine, weak bases that raise the pH of acidic compartments. Measurements of pH documented that S. typhimurium delayed and attenuated acidification of its intracellular compartment. Phagosomes containing S. typhimurium required 4-5 hr to ...

Apoptotic cells generated by programmed cell death are engulfed by phagocytes and enclosed within membrane-bound phagosomes. Maturation of apoptotic cell-containing phagosomes leads to formation of phagolysosomes where cell corpses are degraded. The class III phosphatidylinositol 3-kinase (PI3-kinase) VPS-34 coordinates with PIKI-1, a class II PI3-kinase, to produce PtdIns3P on phagosomes, thus promoting phagosome closure and maturation. Here, we identified UBC-13, an E2 ubiquitin-conjugating enzyme that functions in the same pathway with VPS-34 but in parallel to PIKI-1 to regulate PtdIns3P generation on phagosomes. Loss of ubc-13 affects early steps of phagosome maturation, causing accumulation of cell corpses. We found that UBC-13 functions with UEV-1, a noncatalytic E2 variant, and CHN-1, a U-box-containing E3 ubiquitin ligase, to catalyze K63-linked poly-ubiquitination on VPS-34 both in vitro and in Caenorhabditis elegans. Loss of ubc-13, uev-1, or chn-1 disrupts ubiquitin modification of ...

A prequel to endosomal maturation into late endosomal/lysosomal organelles is Rab conversion (Rink et al., 2005). This term describes a process whereby an organelle synchronously sheds off early endosomal Rab(s) and concomitantly receives the late endosomal Rab, Rab7 (Rink et al., 2005). The signals for this transition are currently unknown (Deretic, 2005). We wondered whether Rab conversion applies to phagosomes, and whether Rab22a, as a candidate terminal recycling Rab involved in cargo and membrane sorting from the early endosome (Mesa et al., 2001; Weigert et al., 2004), could supply or contribute to such signals. To test this, we examined Rab7 acquisition by the mycobacterial phagosome, which was previously shown to exclude this critical late endocytic Rab (Via et al., 1997). Unlike in cells treated with control scrambled siRNA, Rab7 acquisition was increased to 80% on live mycobacterial phagosomes in macrophages in which Rab22a was knocked down by siRNA (Fig. 5). These findings are ...

Nascent phagosomes need to undergo a series of fusion and fission reactions to acquire the microbicidal properties required for the innate immune response. form of RILP lacking the dynein-dynactin-recruiting domain. We conclude that full maturation of phagosomes requires the retrograde emission of tubular extensions which are generated by activation of Rab7 recruitment of RILP and consequent association of phagosomes with microtubule-associated motors. Leukocytes eliminate pathogens and apoptotic cells by in the beginning engulfing them into a phagocytic vacuole. The vacuole which is derived from the plasmalemma needs to undergo extensive remodeling to acquire microbicidal and lytic capabilities (28). Such remodeling also known as maturation entails sequential fusion with numerous components of the endolysosomal pathway and concomitant fission E 2012 events that maintain the vacuolar size nearly constant (1 28 The molecular machinery underlying maturation particularly the E 2012 process of ...

Starvation-induced autophagosomes engulf cytosol and/or organelles and deliver them to lysosomes for degradation, thereby resupplying depleted nutrients. Despite advances in understanding the molecular basis of this process, the membrane origin of autophagosomes remains unclear. Here, we demonstrate that, in starved cells, the outer membrane of mitochondria participates in autophagosome biogenesis. The early autophagosomal marker, Atg5, transiently localizes to punctae on mitochondria, followed by the late autophagosomal marker, LC3. The tail-anchor of an outer mitochondrial membrane protein also labels autophagosomes and is sufficient to deliver another outer mitochondrial membrane protein, Fis1, to autophagosomes. The fluorescent lipid NBD-PS (converted to NBD-phosphotidylethanolamine in mitochondria) transfers from mitochondria to autophagosomes. Photobleaching reveals membranes of mitochondria and autophagosomes are transiently shared. Disruption of mitochondria/ER connections by mitofusin2 ...

Surface where Isolation membrane application will be made should be cleaned from loose soil, oil and other chemicals. Surface defects are repaired with Starfix repair mortar. For a healthy application it is advised to use İzopak water Isolation membrane primer bitumen emulsion as a primer to the surface. Surface where Isolation membrane application will be made should be cleaned from loose soil, oil and other chemicals. Surface defects are repaired with Starfix repair mortar. For a healthy application it is advised to use İzopak water Isolation membrane primer bitumen emulsion as a primer to the surface.. ...

Cecilia Czibener, Nathan M. Sherer, Steven M. Becker, Marc Pypaert, Enfu Hui, Edwin R. Chapman, Walther Mothes, Norma W. Andrews; Ca2+ and synaptotagmin VII-dependent delivery of lysosomal membrane to nascent phagosomes . J Exp Med 2 October 2006; 203 (10): i26. doi: https://doi.org/10.1084/JEM20310OIA26. Download citation file:. ...

M tuberculosis is an intracellular pathogen with the ability to persist in the early phagosomal compartment.2 It arrests phagosome maturation at an early stage and strongly inhibits phagolysosome fusion. The phagolysosome is a rather hostile environment, where many bacterial pathogens are killed. The early phagosome is a less hostile compartment where M tuberculosis can accommodate itself. Yet, arrest of phagosome maturation by M tuberculosis is not complete and some bacteria are killed or at least prohibited from replication through antibacterial mechanisms including reactive oxygen and nitrogen intermediates, which are produced by activated macrophages (fig 1). The different T cell populations produce interferon γ (IFNγ) and hence are of the T helper 1 (Th1) type. This cytokine is the central mediator of macrophage activation. IFNγ synergises with tumour necrosis factor α (TNFα) in activating macrophages. CD4 T cells also produce lymphotoxin α (LTα), which participates in protection ...

You are viewing: Isolation membrane. Isolation membranes, also known as phagophores, are membrane structures involved in autophagosome formation.

Antigen (Ag) crosspresentation by dendritic cells (DCs) involves the presentation of internalized Ags on MHC class I molecules to initiate CD8+ T

TY - JOUR. T1 - The kinetics of phagosome maturation as a function of phagosome/lysosome fusion and acquisition of hydrolytic activity. AU - Yates, Robin M.. AU - Hermetter, Albin. AU - Russell, David G.. PY - 2005. Y1 - 2005. U2 - 10.1111/j.1600-0854.2005.00284.x. DO - 10.1111/j.1600-0854.2005.00284.x. M3 - Article. VL - 6. SP - 413. EP - 420. JO - Traffic. JF - Traffic. SN - 1398-9219. IS - 5. ER - ...

The pathogenesis of mycobacterial infection is associated with an ability to interfere with maturation of the phagosomal compartment after ingestion by macrophages. Identification of the mycobacterial components that contribute to this phenomenon will allow rational design of novel approaches to the treatment and prevention of tuberculosis. Microarray-based screening of a transposon library was used to identify mutations that influence the fate of Mycobacterium bovis bacille Calmette-Guérin (BCG) following uptake by macrophages. A screen based on bacterial survival during a 3-d infection highlighted genes previously implicated in growth of Mycobacterium tuberculosis in macrophages and in mice, together with a number of other virulence genes including a locus encoding virulence-associated membrane proteins and a series of transporter molecules. A second screen based on separation of acidified and non-acidified phagosomes by flow cytometry identified genes involved in mycobacterial control of early

The interaction of (Mtb) with sponsor cell death signaling Flumatinib mesylate pathways is characterized by an initial anti-apoptotic phase followed by a pro-necrotic phase to allow for sponsor cell exit of the bacteria. phagocytic cells Mtb resides within a altered phagosomal compartment and IL2RG inhibits apoptotic sponsor cell death. Recent studies possess shown that Mtb eventually translocates from your phagosomal compartment to the cytosol. This event is definitely followed by the induction of necrotic sponsor cell death allowing the bacteria to exit the sponsor cell and infect naive cell populations. Our study adds to this relatively unexplored aspect of Mtb pathogenesis by exposing the transcriptional repressor of Mtb negatively regulates phagosomal escape and sponsor cell necrosis. We furthermore demonstrate the improved necrosis induction from the Mtb mutant strain deficient in required elevated reactive oxygen species levels within sponsor cell mitochondria and reduced activation of ...

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Trost M., English L., Lemieux S., Courcelles M., Desjardins M., Thibault P.. The ability of macrophages to clear pathogens and elicit a sustained immune response is regulated by various cytokines, including interferon-gamma (IFN-gamma). To investigate the molecular mechanisms by which IFN-gamma modulates phagosome functions, we profiled the changes in composition, abundance, and phosphorylation of phagosome proteins in resting and activated macrophages by using quantitative proteomics and bioinformatics approaches. We identified 2415 phagosome proteins together with 2975 unique phosphorylation sites with a high level of sensitivity. Using network analyses, we determined that IFN-gamma delays phagosomal acquisition of lysosomal hydrolases and peptidases for the gain of antigen presentation. Furthermore, this gain in antigen presentation is dependent on phagosomal networks of the actin cytoskeleton and vesicle-trafficking proteins, as well as Src kinases and calpain proteases. Major ...

In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs). A phagosome is formed by the fusion of the cell membrane around a microorganism or senescent cell. Phagosomes have membrane-bound proteins to recruit and fuse with lysosomes to form mature phagolysosomes. The lysosomes contain hydrolytic enzymes and reactive oxygen species (ROS) which kill and digest the pathogens. Phagosomes can also form in non-professional phagocytes, but they can only engulf a smaller range of particles, and do not contain ROS. The useful materials (e.g. amino acids) from the digested particles are moved into the cytosol, and waste is removed by exocytosis. Phagosome formation is crucial for tissue homeostasis and both innate and adaptive host defense against pathogens. However, some bacteria can exploit phagocytosis as an invasion strategy. They either reproduce inside of the ...

The initial step of autophagosome formation of an omegasome on the endoplasmic reticulum, followed by of elongation of structures called phagophores.[3]. The formation of autophagosomes is controlled by Atg genes through Atg12-Atg5 and LC3 complexes. The conjugate of Atg12-Atg5 also interacts with Atg16 to form larger complexes. Modification of Atg5 by Atg12 is essential for the elongation of the initial membrane.[4]. After the formation of the spherical structure, the complex of ATG12-ATG5:ATG16L1 dissociates from the autophagosome. LC3 is cleaved by ATG4 protease to generate cytosolic LC3. LC3 cleavage is required for the terminal fusion of an autophagosome with its target membrane. LC3 is commonly used as a marker of autophagosomes in immunocytochemistry, because it is the essential part of the vesicle and stays associated until the last moment before its fusion. At first, autophagosomes fuse with endosomes or endosome-derived vesicles. These structures are then called amphisomes or ...

Phagocytosis is the process of taking in relatively large particles by a cell, and is a central mechanism in the tissue remodeling, inflammation, and defense against infectious agents. A phagosome is formed when the specific receptors on the phagocyte surface recognize ligands on the particle surface. After formation, nascent phagosomes progressively acquire digestive characteristics. This maturation of phagosomes involves regulated interaction with the other membrane organelles, including recycling endosomes, late endosomes and lysosomes. The fusion of phagosomes and lysosomes releases toxic products that kill most bacteria and degrade them into fragments. However, some bacteria have strategies to escape the bactericidal mechanisms associated with phagocytosis and survive within host phagocytes ...

Phagocytosis is the process of taking in relatively large particles by a cell, and is a central mechanism in the tissue remodeling, inflammation, and defense against infectious agents. A phagosome is formed when the specific receptors on the phagocyte surface recognize ligands on the particle surface. After formation, nascent phagosomes progressively acquire digestive characteristics. This maturation of phagosomes involves regulated interaction with the other membrane organelles, including recycling endosomes, late endosomes and lysosomes. The fusion of phagosomes and lysosomes releases toxic products that kill most bacteria and degrade them into fragments. However, some bacteria have strategies to escape the bactericidal mechanisms associated with phagocytosis and survive within host phagocytes ...

Phagocytosis is the process of taking in relatively large particles by a cell, and is a central mechanism in the tissue remodeling, inflammation, and defense against infectious agents. A phagosome is formed when the specific receptors on the phagocyte surface recognize ligands on the particle surface. After formation, nascent phagosomes progressively acquire digestive characteristics. This maturation of phagosomes involves regulated interaction with the other membrane organelles, including recycling endosomes, late endosomes and lysosomes. The fusion of phagosomes and lysosomes releases toxic products that kill most bacteria and degrade them into fragments. However, some bacteria have strategies to escape the bactericidal mechanisms associated with phagocytosis and survive within host phagocytes ...

Phagocytosis is the process of taking in relatively large particles by a cell, and is a central mechanism in the tissue remodeling, inflammation, and defense against infectious agents. A phagosome is formed when the specific receptors on the phagocyte surface recognize ligands on the particle surface. After formation, nascent phagosomes progressively acquire digestive characteristics. This maturation of phagosomes involves regulated interaction with the other membrane organelles, including recycling endosomes, late endosomes and lysosomes. The fusion of phagosomes and lysosomes releases toxic products that kill most bacteria and degrade them into fragments. However, some bacteria have strategies to escape the bactericidal mechanisms associated with phagocytosis and survive within host phagocytes ...

This volume details experimental approaches used to investigate phagocytosis and phagosome maturation. Chapters present methods and protocols on quantifying uptake and phagosome maturation using bioph

Autophagy has been postulated to play role in mammalian host defense against fungal pathogens, although the molecular details remain unclear. Here, we show that primary macrophages deficient in the autophagic factor LC3 demonstrate diminished fungicidal activity but increased cytokine production in response to Candida albicans stimulation. LC3 recruitment to fungal phagosomes requires activation of the fungal pattern receptor dectin-1. LC3 recruitment to the phagosome also requires Syk signaling but is independent of all activity by Toll-like receptors and does not require the presence of the adaptor protein Card9. We further demonstrate that reactive oxygen species generation by NADPH oxidase is required for LC3 recruitment to the fungal phagosome. These observations directly link LC3 to the inflammatory pathway against C. albicans in macrophages.. ...

Here, we describe an approach to directly visualize the activity of proteases that are incorporated into the phagosome at different stages of maturation. Only small numbers of phagocytes are required and there is no need to isolate individual endosomal compartments before analysis. This method is sensitive enough to allow an examination of primary cultures of professional APC, including DCs. Furthermore, the use of covalent active site-directed probes in conjunction with electrophoresis ensures specificity. Methods that employ fluorogenic substrates to detect protease activity suffer from the drawback that more than one enzyme can usually cleave a given peptide substrate. Analysis of the delivery of active hydrolases to the phagosome helped clarify both the distribution of cysteine protease activities among the different endocytic organelles and the dynamics of phagosomal maturation in primary cultures of professional APCs.. We validated our method of in vivo labeling of phagosomal proteolytic ...

Innate immunity is vital for protection from microbes and is mediated by humoral effectors, such as cytokines, and cellular immune defenses, including phagocytic cells (e.g., macrophages). After internalization

Pathogens have evolved a range of mechanisms to counteract host defenses, notably to survive harsh acidic conditions in phagosomes. In the case of

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Tony Yeung, Bryan Heit, Jean-Francois Dubuisson, Gregory D. Fairn, Basil Chiu, Robert Inman, Andras Kapus, Michele Swanson, Sergio Grinstein ...

Serine/threonine MAP kinase; involved in regulating maintenance of cell wall integrity, progression through the cell cycle, and nuclear mRNA retention in heat shock; required for mitophagy and pexophagy; affects recruitment of mitochondria to the phagophore assembly site (PAS); regulated by the PKC1-mediated signaling pathway ...

p62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis / Hyunjoo Cha-Molstad; Ji-Eun Yu; Z Feng; S H Lee; Jung Gi Kim; P Yang; B Han; K W Sung; Y D Yoo; Joonsung Hwang; T McGuire; S M Shim; H D Song; S Ganipisetti; N Wang; J M Jang; M J Lee; Seung Jun Kim; Kyung Ho Lee; J T Hong; A Ciechanover; I Mook-Jung; K P Kim; X Q Xie; Y T Kwon; Bo Yeon Kim , 2017 ...

p62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis / Hyunjoo Cha-Molstad; Ji-Eun Yu; Z Feng; S H Lee; Jung Gi Kim; P Yang; B Han; K W Sung; Y D Yoo; Joonsung Hwang; T McGuire; S M Shim; H D Song; S Ganipisetti; N Wang; J M Jang; M J Lee; Seung Jun Kim; Kyung Ho Lee; J T Hong; A Ciechanover; I Mook-Jung; K P Kim; X Q Xie; Y T Kwon; Bo Yeon Kim , 2017 ...

Reactome is pathway database which provides intuitive bioinformatics tools for the visualisation, interpretation and analysis of pathway knowledge.

Reactome is pathway database which provides intuitive bioinformatics tools for the visualisation, interpretation and analysis of pathway knowledge.

Erwig LP, McPhilips KA, Wynes MW, Ivetic A, Ridley AJ, Henson PM. Differential regulation of phagosome maturation in macrophages and dendritic cells mediated by Rho GTPases and ezrin-radixin-moesin (ERM) proteins ...

UniProt ITasser SWISS Models alphafold D3Targets-2019-nCoV Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic. Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes. ...

strong evidence that transcriptional repression plays a major role in regulating GARAPL1/MAP1LC3A levels, and this up-regulation results in an increase in the size of the autophagosome ...

Recently, the fixed-dose combinations (FDC) KIVEXA™ (abacavir/lamivudine) and TRUVADA (tenofovir disoproxil fumarate/emtricitabine) have facilitated the usage of once-daily regimens. However data from head-to-head randomized trials comparing these two FDCs as part of an initial regimen are not available at present. The long-term toxicity profiles of these regimens are of particular importance, as treatment of HIV is currently life-long and therefore, minimizing long-term toxicity and maximizing adherence and duration of regimen maintenance are critical therapy objectives.. The primary endpoint is estimated glomerular filtration rate (GFR), as measured by the modified diet in renal disease (MDRD) equation, a validated estimate of renal function. ...

A fundamental question regarding autophagosome formation is how the shape of the double-membrane autophagosomal vesicle is generated. Here we show that in mammalian cells assembly of an actin scaffold inside the isolation membrane (the autophagosomal precursor) is essential for autophagosomal membrane shaping. Actin filaments are depolymerized shortly after starvation and actin is assembled into a network within the isolation membrane. When formation of actin puncta is disrupted by an actin polymerization inhibitor or by knocking down the actin-capping protein CapZβ, isolation membranes and omegasomes collapse into mixed-membrane bundles. Formation of actin puncta is PtdIns(3)P dependent, and inhibition of PtdIns(3)P formation by treating cells with the PI(3)K inhibitor 3-MA, or by knocking down Beclin-1, abolishes the formation of actin puncta. Binding of CapZ to PtdIns(3)P, which is enriched in omegasomes, stimulates actin polymerization. Our findings illuminate the mechanism underlying

The goal of this project is to unveil how membranes are assembled into autophagosomes. We will uniquely combine yeast Saccharomyces cerevisiae genetics and immuno-electron tomography to reach this objective. At first, we will devise a novel electron tomography protocol to preserve yeast autophagosomal membranes near their native state and be able immunolabel them. Subsequently, we will exploit this procedure to develop a model about how autophagosomal membranes are assembled into autophagosomes by analysing the precursor structures accumulated in yeast autophagy mutants. This unique experimental system will allow us visualizing the formation of autophagosomes through 3-dimentional images with ultrastructural resolution, and determine the distribution of Atg proteins, thus acquitting insights into their function ...

Phagocytosis involves the internalization of extracellular material by invagination of the plasma membrane to form intracellular vesicles called phagosomes, which have functions that include pathogen degradation. The degradative properties of phagosomes are thought to be conferred by sequential fusion with endosomes and lysosomes; however, this maturation process has not been studied in vivo. We employed Drosophila hemocytes, which are similar to mammalian professional macrophages, to establish a model of phagosome maturation. Adult Drosophila females, carrying transgenic Rab7-GFP endosome and Lamp1-GFP lysosome markers, were injected with E. coli DH5α and the hemocytes were collected at 15, 30, 45 and 60 minutes after infection. In wild-type females, E. coli were detected within enlarged Rab7-GFP positive phagosomes at 15 to 45 minutes after infection; and were also observed in enlarged Lamp1-GFP positive phagolysosomes at 45 minutes. Two-photon imaging of hemocytes in vivo confirmed this vesicle

Intestinal epithelial cells (IECs) play a key role in regulating immune responses and controlling infection. However, the direct role of IECs in restricting pathogens remains incompletely understood. Here, we provide evidence that IL-22 primed intestinal organoids derived from healthy human induced pluripotent stem cells (hIPSCs) to restrict Salmonella enterica serovar Typhimurium SL1344 infection. A combination of transcriptomics, bacterial invasion assays, and imaging suggests that IL-22-induced antimicrobial activity is driven by increased phagolysosomal fusion in IL-22-pretreated cells. The antimicrobial phenotype was absent in hIPSCs derived from a patient harboring a homozygous mutation in the IL10RB gene that inactivates the IL-22 receptor but was restored by genetically complementing the IL10RB deficiency. This study highlights a mechanism through which the IL-22 pathway facilitates the human intestinal epithelium to control microbial infection.

Phagosome formation and subsequent maturation are complex sequences of events that involve actin cytoskeleton remodeling and membrane trafficking. Here, we demonstrate that the Ras‐related protein Rab35 is involved in the early stage of FcγR‐mediated phagocytosis in macrophages. Live‐cell image analysis revealed that Rab35 was markedly concentrated at the membrane where IgG‐opsonized erythrocytes (IgG‐Es) are bound. Rab35 silencing by RNA interference (RNAi) or the expression of GDP‐ or GTP‐locked Rab35 mutant drastically reduced the rate of phagocytosis of IgG‐Es. Actin‐mediated pseudopod extension to form phagocytic cups was disturbed by the Rab35 silencing or the expression of GDP‐Rab35, although initial actin assembly at the IgG‐E binding sites was not inhibited. Furthermore, GTP‐Rab35‐dependent recruitment of ACAP2, an ARF6 GTPase‐activating protein, was shown in the phagocytic cup formation. Concomitantly, overexpression of ACAP2 along with GTP‐locked Rab35 ...

Given the diversity of autophagy targets and regulation, it is important to characterize autophagy in various cell types and conditions. We used a primary myocyte cell culture system to assay the role of putative autophagy regulators in the specific context of skeletal muscle. By treating the cultures with rapamycin (Rap) and chloroquine (CQ) we induced an autophagic response, fully suppressible by knockdown of core ATG genes. We screened D. melanogaster orthologs of a previously reported mammalian autophagy protein-protein interaction network, identifying several proteins required for autophagosome formation in muscle cells, including orthologs of the Rab regulators RabGap1 and Rab3Gap1. The screen also highlighted the critical roles of the proteasome and glycogen metabolism in regulating autophagy. Specifically, sustained proteasome inhibition inhibited autophagosome formation both in primary culture and larval skeletal muscle, even though autophagy normally acts to suppress ubiquitin ...

Dengue virus (DENV)[seventeen], hepatitis B virus (HBV) [31] and influenza A virus (IAV)[32] not only have been revealed to induce autophagy but also upregulate autophagy to market virus replication. Curiously, human parainfluenza virus sort 3 (HPIV3)[33], rotavirus and human immunodeficiency virus sort 1(HIV-one)[34] have been reported to induce autophagy but to block the fusion in between autophagosomes and lysosomes, leading to autophagosome accumulation to 859212-16-1 supplier facilitate viral generation. In this study, we found that CA16 an infection could induce autophagy. Nevertheless, the autophagosomes unsuccessful to fuse with the lysosomes, major to considerable autophagosome accumulation. The offered data indicate that the gathered autophagosomes could in change favor the reproduction of RNA viruses by many mechanisms. Initial, autophagosomes that are unsuccessful to fuse with lysosomes might stop the freshly fashioned virions or viral RNA from degrading or currently being processed ...

The interest on autophagy, an evolutionarily conserved process in eukaryotes, has enormously increased in the last years, since the malfunctioning of autophagy is involved in many diseases such as cancer or neurodegenerative states. Autophagosome formation is the key process in autophagy. Despite extensive work, the model of autophagosome formation is not yet fully established. Some important questions remain to be elusive, such as where the bona fide marker protein of autophagosome, LC3, is lipidated, how lipidated LC3 functions in autophagosome formation, and how the proteins for LC3 lipidation and delipidation are involved in autophagosome formation.. Although genetic approaches have been powerful to dissect autophagosome formation process, intrinsic limitations include the lack of acute manipulation in protein activity. We will prepare semi-synthetic LC3 and lipidated LC3 proteins and use them to monitor dynamics of autophagosome formation in vitro and in cells. The semi-synthetic LC3 ...

Salmonella species are facultative intracellular pathogens. Following entry into mammalian host cells, they reside in membrane-bound vacuoles, resist killing, and replicate. In this work, we investigated the importance of phagosomal pH in the ability of Salmonella typhimurium to survive and replicate within macrophages. Intraphagosomal pH was measured in situ by recording the fluorescence intensity of a pH-sensitive probe, DM-NERF dextran. The majority of vacuoles containing S. typhimurium (live, heat killed, or formalin fixed) acidified from pH , or = 6.0 to between pH 4.0 and 5.0 within 60 min after formation. In contrast, Mycobacterium avium-containing vacuoles failed to acidify even at later time points. Acidification of S. typhimurium-containing vacuoles was completely blocked by treatment of host cells with bafilomycin A, a specific inhibitor of vacuolar proton-ATPases. Bafilomycin inhibition of vacuolar acidification from the onset of infection significantly decreased the survival of S. ...

Autophagosomes are double-membrane vesicles characteristic of macroautophagy, a degradative pathway for cytoplasmic material and organelles terminating in the lysosomal or vacuole compartment for mammals and yeast, respectively. This highly dynamic, multi-step process requires significant membrane reorganization events at different stages of the macroautophagic process. Such events include exchange and flow of lipids and proteins between membranes and vesicles (e.g., during initiation and growth of the phagophore), vesicular positioning and trafficking within the cell (e.g., autophagosome location and movement) and fusion of autophagosomes with the boundary membranes of the degradative compartment. Here, we review current knowledge on the contribution of different organelles to the formation of autophagosomes, their trafficking and fate within the cell. We will consider some of the unresolved questions related to the molecular mechanisms that regulate the

Invasive infections by the human pathogenic fungus Aspergillus fumigatus start with the outgrowth of asexual, airborne spores (conidia) into the lung tissue of immunocompromised patients. The resident alveolar macrophages phagocytose conidia, which end up in phagolysosomes. However, A. fumigatus conidia resist phagocytic degradation to a certain degree. This is mainly attributable to the pigment 1,8-dihydroxynaphthalene (DHN) melanin located in the cell wall of conidia, which manipulates the phagolysosomal maturation and prevents their intracellular killing. To get insight in the underlying molecular mechanisms, we comparatively analyzed proteins of mouse macrophage phagolysosomes containing melanized wild-type (wt) or non-melanized pksP mutant conidia. For this purpose, a protocol to isolate conidia-containing phagolysosomes was established and a reference protein map of phagolysosomes was generated. We identified 637 host and 22 A. fumigatus proteins that were differentially abundant in the ...

The GTPase Ypt1 and its mammalian homolog Rab1 regulate three different trafficking events: autophagy, ER-Golgi, and intra-Golgi traffic (12). During autophagy, Ypt1 is recruited to the phagophore by the TRAPPIII complex, one of three multimeric Ypt1/Rab1 GEFs that localize to distinct cellular locations (12). These complexes share several essential subunits that are required for GEF activity. The TRAPPIII-specific subunit Trs85 specifically directs TRAPPIII to the phagophore where it recruits and activates Ypt1 on the autophagy pathway (14).. To determine where on the autophagy pathway TRAPPIII and Ypt1 act, we screened all known autophagy-deficient atg mutants for defects in the recruitment of Trs85 to the PAS. This screen revealed that the recruitment of TRAPPIII to the PAS is dependent on Atg17 and suggested that Ypt1 and its GEF act in the induction step of the pathway. Five Atg proteins act in induction: Atg1, Atg13, Atg17, Atg29, and Atg31 (6, 9). Of these, only Atg1 is recruited to the ...

Analyses of a developmentally regulated Drosophila myofiber remodeling program provide insight into induced autophagy required for T-tubule membrane reorganization, and uncover a conserved Rab2 role in autophagosome-lysosome fusion.

Cells undergo autophagy or self-eating as a means of recycling their constituents in order to maintain homeostasis. Autophagy is up regulated by stress, including amino acid deprivation for which it is best characterised. Upon amino acid starvation double or multiple lamellar vesicles termed autophagic vacuoles (AV) or autophagosomes appear throughout the cells cytoplasm. From their content they can be seen to have sequestered cytoplasm, often including organelles. Screens for autophagy defective mutants in Saccharomyces cerevisiae resulted in the AuTophaGy (ATG) genes. I have studied the ubiquitously expressed mammalian orthologue of Atg9p (Atg9Ll), a multi-spanning transmembrane protein shown to be essential in yeast for autophagy. I studied Atg9Ll in the hope that, as it is a multi-spanning transmembrane protein, it might provide clues as to the origin of the autophagosomal membranes. Initially addressing the proteins topology I show that both the N-and C-termini of Atg9L1 are cytosolic, ...

Macroautophagy, a major pathway for organelle and protein turnover, has been implicated in the neurodegeneration of Alzheimers disease (AD). The basis for the profuse accumulation of autophagic vacuoles (AVs) in affected neurons of the AD brain, however, is unknown. In this study, we show that constitutive macroautophagy in primary cortical neurons is highly efficient, because newly formed autophagosomes are rapidly cleared by fusion with lysosomes, accounting for their scarcity in the healthy brain. Even after macroautophagy is strongly induced by suppressing mTOR (mammalian target of rapamycin) kinase activity with rapamycin or nutrient deprivation, active cathepsin-positive autolysosomes rather than LC3-II-positive autophagosomes predominate, implying efficient autophagosome clearance in healthy neurons. In contrast, selectively impeding late steps in macroautophagy by inhibiting cathepsin-mediated proteolysis within autolysosomes with cysteine- and aspartyl-protease inhibitors caused a marked

Sorting of luminal and membrane proteins into phagosomes is critical for the immune function of this organelle. However, little is known about the mechanisms that contribute to the spatiotemporal regulation of this process. Here, we investigated the role of the proneurotrophin receptor sortilin during phagosome maturation and mycobacterial killing. We show that this receptor is acquired by mycobacteria-containing phagosomes via interactions with the adaptor proteins AP-1 and GGAs. Interestingly, the phagosomal association of sortilin is critical for the delivery of acid sphingomyelinase (ASMase) and required for efficient phagosome maturation. Macrophages from Sort1(-/-) mice are less efficient in restricting the growth of Mycobacterium bovis BCG and M. tuberculosis. In vivo, Sort1(-/-) mice showed a substantial increase in cellular infiltration of neutrophils in their lungs and higher bacterial burden after infection with M. tuberculosis. Altogether, sortilin defines a pathway required for ...

Candida glabrata currently ranks as the second most frequent cause of invasive candidiasis. Our previous work has shown that C. glabrata is adapted to intracellular survival in macrophages and replicates within non-acidified late endosomal-stage phagosomes. In contrast, heat killed yeasts are found in acidified matured phagosomes. In the present study, we aimed at elucidating the processes leading to inhibition of phagosome acidification and maturation. We show that phagosomes containing viable C. glabrata cells do not fuse with pre-labeled lysosomes and possess low phagosomal hydrolase activity. Inhibition of acidification occurs independent of macrophage type (human/murine), differentiation (M1-/M2-type) or activation status (vitamin D3 stimulation). We observed no differential activation of macrophage MAPK or NFκB signaling cascades downstream of pattern recognition receptors after internalization of viable compared to heat killed yeasts, but Syk activation decayed faster in macrophages ...

Autophagy is a catabolic process that results in the degradation of bulk cytoplasmic contents within autophagosomes and lysosomes. Two human Atg2 homologs (Atg2A, Atg2B) are critical for autophagosome formation as silencing of both results in the accumulation of unclosed autophagic structures. Starvation-induced autophagy targets Atg2A to the initiation site of autophagosome biogenesis, where it associates with DFCP1, WIPI-1, and other autophagy- related proteins. Atg2 proteins also function in lipid droplet metabolism as depletion of both Atg2A and AtgB results in changes in the size, number, and distribution of lipid droplets. An increase in Atg2A expression during etoposide- and doxorubicin-induced apoptosis suggests that Atg2A may be a useful indicator of topoisomerase II inhibitor-mediated apoptosis.. ...

Autophagy is a well-conserved catabolic process essential for cellular homeostasis. First described in yeast as an adaptive response to starvation, this pathway is also present in higher eukaryotes, where it is triggered by stress signals such as damaged organelles or pathogen infection. Autophagy is characterized at the cellular level by the engulfment of portions of the cytoplasm in double-membrane structures called autophagosomes. Autophagosomes fuse with lysosomes, resulting in degradation of the inner autophagosomal membrane and luminal content. This process is coordinated by complex molecular systems, including the ATG8 ubiquitin-like conjugation system and the ATG4 cysteine proteases, which are implicated in the formation, elongation, and fusion of these autophagic vesicles. In this Review, we focus on the diverse functional roles of the autophagins, a protease family formed by the four mammalian orthologs of yeast Atg4. We also address the dysfunctional expression of these proteases in ...

Autophagy is an evolutionary conserved eukaryotic bulk degradation pathway that results in regulated cellular clearance and secures cellular survival. Autophagic dysfunction has been found to be associated with various human diseases including cancer and neurodegeneration. Aiming to develop therapeutics capable to cure age-related human diseases, the molecular details of autophagy are now becoming understood.. We identified the human WIPI gene family (WIPI-1, -2, -3, and -4) and have begun to establish that WIPI genes are aberrantly expressed in a variety of human cancers (Proikas-Cezanne et al., Oncogene 2004). Using biochemical techniques coupled with confocal and electron microscopy we have demonstrated that WIPI-1 (Atg18 in S. cerevisiae) specifically binds PI(3)P at the onset of autophagy and is essential for autophagosome formation. Upon binding to PI(3)P, WIPI-1 protein accumulation at autophagosomal membranes (WIPI-1 puncta-formation) can be visualized by fluorescent microscopy, ...

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be

Regulator of mitophagy through the upstream regulation of the RNF41/NRDP1-PRKN pathway. Mitophagy is a selective form of autophagy necessary for mitochondrial quality control. The RNF41/NRDP1-PRKN pathway regulates autophagosome-lysosome fusion during late mitophagy. May protect RNF41/NRDP1 from proteosomal degradation, RNF41/NRDP1 which regulates proteosomal degradation of PRKN. Plays a key role in beta cells functions by regulating mitophagy/autophagy and mitochondrial health.

Strains of Escherichia coli persist within the human gut as normal commensals, but are frequent pathogens and can cause recurrent infection. Here we show that, in contrast to E. coli subjected to opsonic interactions stimulated by the hosts immune response, E. coli that bind to the macrophage surface exclusively through the bacterial lectin FimH can survive inside the cell following phagocytosis. This viability is largely due to the attenuation of intracellular free-radical release and of phagosome acidification during FimH-mediated internalization, both of which are triggered by antibody-mediated internalization. This different processing of non-opsonized bacteria is supported by morphological evidence of tight-fitting phagosomes compared with looser, antibody-mediated phagosomes. We propose that non-opsonized FimH-expressing E. coli co-opt internalization of lipid-rich microdomains following binding to the FimH receptor, the glycosylphosphatidylinositol-linked protein CD48, because (1) the sterol

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be ...

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be ...

Bacterial and parasitic intracellular pathogens or their secreted products have been shown to induce host cell transcriptional responses, which may benefit the host, favour the microorganism or be unrelated to the infection. In most instances, however, it is not known if the host cell nucleus is proximately required for the development of an intracellular infection. This information can be obtained by the infection of artificially enucleated host cells (cytoplasts). This model, although rather extensively used in studies of viral infection, has only been applied to few bacterial pathogens, which do not include Mycobacterium spp. Here, we investigate the internalization, phagosome biogenesis and survival of M. smegmatis in enucleated type II alveolar epithelial cells. Cytoplasts were infected with M. smegmatis, but the percentage of infection was significantly lower than that of nucleated cells. Scanning electron microscopy indicated that in both cells and cytoplasts, bacteria were internalized ...

Ubiquitin-like modifier involved in formation of autophagosomal vacuoles (autophagosomes). Plays a role in mitophagy which contributes to regulate mitochondrial quantity and quality by eliminating the mitochondria to a basal level to fulfill cellular energy requirements and preventing excess ROS production. Whereas LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation. Promotes primary ciliogenesis by removing OFD1 from centriolar satellites via the autophagic pathway ...

Autophagy is a cellular process mediating degradation of bulk cytoplasm, long-lived proteins and entire organelles. In this process, double-membrane vesicles, the autophagosomes, wrap around portions of cytosol and transport them to the lysosome for degradation. Several molecules participate in autophagosome nucleation and elongation, including various components of the class III PI3K complex, such as Beclin 1 and Ambra1 (. Activating Molecule in Beclin 1-Regulated Autophagy), which has been recently characterized in our laboratory (1, 2). Any genetic or pharmacological alteration in this process impairs the cell survival rate or cell metabolism, thereby affecting tissue homeostasis (3). Many neurodegenerative conditions, for example, can be traced back to defective autophagy and autophagy has also been identified as a crucial process in oncogenesis and cancer progression. Several autophagy-related proteins have tumor suppressor activity (Beclin 1, Atg5, Bif-1, Atg4C, UVRAG) and some autophagy ...

The fusion of lysosomes to phagosomes was observed under high voltage electron microscopy, in 4μm thick rat retinal sections with the aid of acid phosphatase cytochemistry. The study of thick sections facilitates the observation of the moment of fusion in stereo view from two tilted pictures. From this study, the contents of the lysosome pored into the phagosome through the orifice, shortly after the collision of the two organelles. The hydrolytic enzymes such as acid phosphatase spread in a sheet under the limiting membrane of the phagosome to finally form a balloon of the reaction product. In some case the ballooning appeared to be doubled. The outer skin of the reaction product may be the result of a wrapping mechanism of phagolysosomes.. ...

Macroautophagy - This is widely considered to be the most used pathway of autophagy in the body. It deals with the recycling of dysfunctional organelles and proteins which may have been damaged or incorrectly folded during their synthesis. The process starts with a piece of cellular machinery termed the isolation membrane or phagophore. This is a double membrane structure that elongates and encloses part of the cytoplasm, as well as the target organelles or proteins. The resulting specialised vesicle is termed an autophagosome. The autophagosome then migrates to a lysosome to which it fuses via the outer membrane. It is important to note the outer membrane stays intact thus keeping the contents and Hydrolases within the autolysosome for recycling[8][9]. Microautophagy - This process differs from macroautophagy as it is only concerned with the degradation and recycling of cytoplasm in the cell. It also uses a different mechanism. No autophagosome is formed as the lysosome itself directly ...

Macroautophagy - widely considered to be the most used pathway of autophagy in the body. It deals with the recycling of dysfunctional organelles and proteins which may have been damaged or incorrectly folded during their synthesis. The process starts with a piece of cellular machinery termed the isolation membrane or phagophore which is a double membrane structure that elongates and encloses part of the cytoplasm as well as the target organelles or proteins. This structure is termed an autophagosome. The autophagosome then migrates to a lysosome to which it fuses with via the outer membrane. It is important to note the outer membrane stays intact thus keeping the contents and hydrolyses within the autolysosome for recycling[7][8]. Microautophagy - This differs from macroautophagy as it is only concerned with the degradation and recycling of cytoplasm. It also differs in its mechanism. No autophagosome is formed as the lysosome itself directly degrades the cytoplasm by inward invaginations ...

By M. A. Hayat. Understanding the significance and necessity of the function of autophagy in health and wellbeing and ailment is key for the stories of melanoma, getting older, neurodegeneration, immunology, and infectious illnesses. complete and updated, this publication deals a worthwhile consultant to those mobile approaches when inciting researchers to discover their almost certainly very important connections. Volume 7 presents assurance of the newest advancements in autophagosome biogenesis and rules; the position of autophagy in protein quality controls; and the function of autophagy in apoptosis. awareness is given to autophagy within the cardiovascular method, with specific insights into the function of autophagy in atherosclerosis and the particular habit of autophagy within the sinoatrial node. state of the art findings within the relationships among autophagy and way of life are explored with the law of macroautophagy in keeping with workout, in addition to the promoting of ...

Integral membrane proteins (natural resistance associated macrophage proteins), of the solute carrier family, expressed only in cells of the myeloid series and recruited to the phagosome membrane following phagocytosis. Mutations in Nramp1 (SLC11A1, 550 aa) impair macrophage killing of intracellular parasites such as Mycobacteria, Salmonella, and Leishmania and are also associated with the onset of rheumatoid arthritis. Nramp2 (SLC11A2, 568 aa) is very similar to Nramp1 but more widely expressed and is known to be involved in cellular iron absorption at the luminal surface of the duodenum. ...

2014 Project header}} =Phagocytosis= [[File:Leukocyte_phagocytosis_of_yeast.jpg,thumb,right,300px,Phagocytosis of yeast by a Leukocyte]] ==Introduction== Phagocytosis is a crucial defence mechanism of the innate immune response which eliminates debris and pathogens,ref name=PMID18085665>,pubmed>18085665,/pubmed>,/ref>. Phagocytosis is a specialised type of endocytosis where large (≥0.5 μm),ref name=PMID10358769>,pubmed>10358769,/pubmed>,/ref> solid particles are internalised through the receptor-mediated engulfment of membrane-derived vesicles called phagosomes,ref name=PMID21783028>,pubmed>21783028,/pubmed>,/ref>. After the vesicles detach from the plasma membrane (scission), the phagosome matures by fusing with endosomes and lysosomes (which contain hydrolytic enzymes) to form a phagolysosome. The hydrolytic enzymes in the phagolysosome break down the internalised solid particles. The mechanism behind Phagocytosis is clathrin (a protein that plays a major role in formation of coated ...

Inhibits PIK3C3 activity; under basal conditions negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy. Negatively regulates endosome maturation and degradative endocytic trafficking and impairs autophagosome maturation process. Can sequester UVRAG from association with a class C Vps complex (possibly the HOPS complex) and negatively regulates Rab7 activation (PubMed:20974968, PubMed:21062745).

Tuberculosis, which most often affects the lungs and leads to respiratory impairment, is caused by the acid-fast bacterium, M. tuberculosis. The bacterium is particularly virulent due to its ability to prevent phagosome-lysosome fusion after engulfment by macrophages. Since a phagolysosome is not formed, the bacterium is able to escape degradation. However, when the adaptive immune system is activated, TH1 cells secrete IFN-gamma, which overcomes this bacterial defense mechanism. IFN-gamma also causes macrophages to differentiate into epithelioid cells, which may then combine to create large, multi-nucleated, giant cells (Langhans cells). This eventually leads to the formation of the granuloma that is characteristic of a tuberculosis infection ...

Autophagy is an intracellular bulk degradation system that is found ubiquitously in eukaryotes. Autophagy is responsible for the degradation of most long-lived proteins and some organelles. Cytoplasmic constituents, including organelles, are sequestered into double-membraned autophagosomes, which su …

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Wu, Y. (Contributor), Wu, W. (Contributor), Lin, L. (Contributor), Liu, C. (Contributor), Ho, S. (Contributor), Wang, B. (Contributor), Huang, B. (Contributor), Yeh, Y. (Contributor), Chiu, H. (Contributor), Yang, W. (Contributor), Wang, Y. (Contributor) (四月 27 2018). Additional file 3: of Bortezomib enhances radiosensitivity in oral cancer through inducing autophagy-mediated TRAF6 oncoprotein degradation. Unknown Publisher. 10.6084/m9.figshare.6198044.v1 ...

Autophagy is a catabolic process whereby damaged organelles and proteins are sequestered into autophagic vesicles, then degraded through fusion with lysosomes and reused as metabolic precursors. While autophagy can suppress tumorigenesis in normal tissues, stimulation of autophagy in established tumors promotes tumor cell survival under stressful metabolic and environmental conditions and can serve as a mechanism of treatment resistance. Yang and colleagues review the role of autophagy in cancer biology and discuss how autophagy can be exploited as a therapeutic target. While most cancer therapeutics induce autophagy, the functional consequence of autophagy induction in the context of cancer therapy continues to emerge.. ...

Scott RC, et al. (2007) Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death. Curr Biol 17(1):1-11 BACKGROUND: To survive starvation and other forms of stress, eukaryotic cells undergo a lysosomal process of cytoplasmic degradation known as autophagy. Autophagy has been implicated in a number of cellular and developmental processes, including cell-growth control and programmed cell death. However, direct evidence of a causal role for autophagy in these processes is lacking, resulting in part from the pleiotropic effects of signaling molecules such as TOR that regulate autophagy. Here, we circumvent this difficulty by directly manipulating autophagy rates in Drosophila through the autophagy-specific protein kinase Atg1. RESULTS: We find that overexpression of Atg1 is sufficient to induce high levels of autophagy, the first such demonstration among wild-type Atg proteins. In contrast to findings in yeast, induction of autophagy by Atg1 is dependent on its ...

Phagocytosis requires receptor-mediated recognition of particles, usually in the guise of infectious agents and apoptotic cells. Phagosomes fuse with lysosomes to generate phagolysosomes, which play a key role in enzymatic digestion of the internaliz

Beclin 2 plays a critical role in metabolic regulation and obesity, but its functions in innate immune signaling and cancer development remain largely unknown. Here, we identified Beclin 2 as a critical negative regulator of inflammation and lymphoma development. Mice with homozygous ablation of BCL2-interacting protein 2 (Becn2) developed splenomegaly and lymphadenopathy and markedly increased ERK1/2 and NF-κB signaling for proinflammatory cytokine production. Beclin 2 targeted the key signaling kinases MEKK3 and TAK1 for degradation through an ATG9A-dependent, but ATG16L/Beclin 1/LC3-independent, autophagic pathway. Mechanistically, Beclin 2 recruited MEKK3 or TAK1 through ATG9A to form a complex (Beclin 2-ATG9A-MEKK3) on ATG9A+ vesicles upon ULK1 activation. Beclin 2 further interacted with STX5 and STX6 to promote the fusion of MEKK3- or TAK1-associated ATG9A+ vesicles to phagophores for subsequent degradation. Importantly, Becn2-deficient mice had a markedly increased incidence of lymphoma ...

Autophagy (Greek, self-eating) is an evolutionarily conserved homeostatic process by which cytoplasmic components are sequestered into double-membraned vesicl...