Semantic Scholar extracted view of Histochemical indications for lysosomal localization of heavy metals in normal rat brain and liver. by Annika Brun et al.
Diril, M. K., Schmidt, S., Krauß, M., Gawlik, V., Joost, H.-G., Schürmann, A., Haucke, V. and Augustin, R. (2009), Lysosomal localization of GLUT8 in the testis - the EXXXLL motif of GLUT8 is sufficient for its intracellular sorting via AP1- and AP2-mediated interaction. The FEBS Journal, 276: 3729-3743. doi: 10.1111/j.1742-4658.2009.07089.x ...
View Notes - Lecture 13 11 from BICD 110 at UCSD. Lecture 13 11/02/07 Golgi Structure/Function, Lysosome, Exocytosis Glycosylation Protects lysosome membrane proteins from autodegradation
Recent data both from cell-free experiments and from cultured cells have shown that lysosomes can fuse directly with late endosomes to form a hybrid organelle. This has a led to a hypothesis that dense core lysosomes are in essence storage granules for acid hydrolases and that, when the former fuse with late endosomes, a hybrid organelle for digestion of endocytosed macromolecules is created. Lysosomes are then re-formed from hybrid organelles by a process involving condensation of contents. In this Commentary we review the evidence for formation of the hybrid organelles and discuss the current status of our understanding of the mechanisms of fusion and lysosome re-formation. We also review lysosome biosynthesis, showing how recent studies of lysosome-like organelles including the yeast vacuole, Drosophila eye pigment granules and mammalian secretory lysosomes have identified novel proteins involved in this process. ...
Lysosomes degrade and recycle transported cellular components and internalized material by fusing with autophagosomes, phagosomes, and late endosomes. The resulting lysosomal breakdown products are used to generate new macromolecules and to provide energy in response to the nutritional needs of the cell. Recently, lysosome functions were expanded to include roles in nutrient sensing and energy metabolism (4). In this study, we report that the exposure of macrophages to LPS or heat-killed bacteria raises AGS3 levels. The increases in AGS3 reduced signaling through the mTOR pathway. However, in a nutrient-replete state this did not lead to a substantive increase in autophagy, but it did facilitate the nuclear translocation of TFEB, which transcriptionally activates many of the genes involved in lysosomal biogenesis and function. The subsequent increase in lysosomal biogenesis/function helped macrophages to resist intracellular infections by several strains of antibiotic-resistant ...
In many cases, apoptosis may be initiated by a minor lysosomal destabilization, which some time later is followed by a secondary, more pronounced, lysosomal rupture. After exposure to low concentrations of sphingosine, a lysosomotropic detergent, Jurkat and J774 cells underwenr apoptotic cell death, while cells exposed to higher concentrations of this agent showed necrosis. Sphingosine-induced apoptosis was partly prevented by the inhibitors of lysosomal aspartic or cysteine proteases, pepstatin A or E64d. Under these conditions, caspase-3 like activity was reduced 40-55%, suggesting that lysosomal enzymes could be upstream activators of caspase-3.. In J774 cells over-expressing Bcl-2, the early oxidant-induced lysosomal destabilization takes place, but the delayed secondary lysosomal rupture and ensuing apoptosis are both suppressed. Phosphorylation of Bcl-2 seems to be required for this anti-apoptotic effect because the protection is amplified by pre-treatment with phorbol 12-myristate ...
Lysosomes are one of the major degradative organelles in eukaryotic cells that carry out diverse cellular functions. Lysosomes show highly dynamic behaviors, including homotypic and heterotypic fusions, fission, and formation/reformation, which itself involves budding, extension, and scission. We carried out an unbiased forward mutational screen to identify novel regulators of lysosome dynamics and/or function; this screen is based on the degradation of a substrate, GFP, that is endocytosed by scavenger cells in worms. We identified cup-5 and six additional proteins that have lysosomal functions in C. elegans coelomocytes. CUP-16 is only conserved in the genus Caenorhabditis, and likely functions in endocytic uptake at the plasma membrane and in lysosomal degradation. Besides CUP-16, five of the mammalian homologs of the other CUP proteins, CIC-7, OSTM1, PLEKHM1, Cystinosin, and TRPML1, had been previously implicated in lysosome biology, thus validating this approach (Bach 2001; Lange et al. ...
The mechanisms involved in radiation-induced cellular injury and death remain incompletely understood. In addition to the direct formation of highly reactive hydroxyl radicals (HO.) by radiolysis of water, oxidative stress events in the cytoplasm due to formation of H2O2 may also be important. Since the major pool of low-mass redox-active intracellular iron seems to reside within lysosomes, arising from the continuous intralysosomal autophagocytotic degradation of ferruginous materials, formation of H2O2 inside and outside these organelles may cause lysosomal labilization with release to the cytosol of lytic enzymes and low-mass iron. If of limited magnitude, such release may induce reparative autophagocytosis, causing additional accumulation of redox-active iron within the lysosomal compartment. We have used radio-resistant histiocytic lymphoma (J774) cells to assess the importance of intralysosomal iron and lysosomal rupture in radiation-induced cellular injury. We found that a 40 Gy ...
The exact mechanism by which the atherogenic lipids oxLDL and CC perturb lysosomal function is not known. Oxidized LDL is taken up by macrophage scavenger receptors and is trafficked to the endolysosomal compartment. Oxidized LDL can then bind and inactivate cathepsins with high affinity,30 inactivate other proteases including the Naβ Gases,31 and produce a form of apolipoproteinB that is highly resistant to hydrolysis.32,33 OxLDL has also been demonstrated in endothelial and smooth muscle cells to inhibit activity and expression of the enzyme crucial to cholesterol ester hydrolysis, LIPA.34 Most recently, the formation of cholesterol microcrystals and ensuing disruption of lysosomal integrity has directly been linked to the buildup of oxLDL in the lysosomal compartment.14 Such a mechanism would favor the notion that the mechanism of lysosomal dysfunction mediated by oxLDL and larger CC lies in a continuum (with the oxLDL pool eventually precipitating as insoluble crystals). Our data support ...
One contributing factor to the increased ability of more stable antigens to elicit immune responses is that the restricted susceptibility to lysosomal proteolysis favored the production of peptide-MHC class II complexes by DCs, at least in vitro (Fig. 2 E and Fig. 4 D). In addition, and just as important in an in vivo setting, we found that the increased stability to lysosomal proteolysis also favored the retention of antigens captured by DCs to lymphoid organs. 16 h after a single intradermal injection, the stable forms of RNase (Alexa 488-RNase-A) could be detected in CD11c+ DCs in the draining lymph nodes (Fig. 1 D). In contrast, the rapidly degraded form (Alexa 647-RNase-S) was barely detectable under the same conditions (Fig. 1 D). Combined with the fact that differential immunogenicity was observed by adoptively transferring DCs containing either RNase-A or RNase-S (Fig. 2 D), these results strongly suggest that at least one effect of decreased susceptibility to proteolysis is to ...
The lack or complexity of high resolution technologies and the need for labelled compound derivatives represents a major limitation on the study of intracellular distribution dynamics of pharmacological agents. The intrinsic, label-free and organelle-specific fluorescence activity of nintedanib presented in this study provides a powerful tool to dissect intracellular accumulation and distribution dynamics of this clinically approved small molecule TKI. The observation that lysosomal alkalization via V-ATPase inhibition sensitized lung cancer cells towards nintedanib suggests that protonation-based lysosomal sequestration represents a cell-intrinsic protection mechanism against this FGFR inhibitor. In accordance, various chemotherapeutic agents including doxorubicin, mitoxantrone and vincristine but also TKIs such as gefitinib, lapatinib and sunitinib have been reported to be subject to inactivating lysosomal sequestration [23, 30]. Together, these findings support a yet underestimated central ...
EIPA-modulated retrograde movement of lysosomes depended on the activity of Rab7, a GTPase known to traffic late endosomes and lysosomes towards the nucleus (Johansson et al., 2007) and the Rab7 effector RILP, which is similar to the mechanism of Troglitazone-induced retrograde lysosome trafficking (Steffan and Cardelli, 2010). In fact, lysosomes in Rab7-KD- and DN-RILP-expressing cells were more peripherally located than in vector control cells. Also, HGF-induced invasion by Rab7-KD cells was not blocked by EIPA, in contrast to control cells. Finally, Fig. 6 demonstrates that Rab7-KD cells were more invasive and secreted more cathepsin B than control cells in the absence of HGF. We conclude that a more peripheral cellular location of lysosomes may be important in regulating invasion, and that EIPA blocks invasion by stimulating retrograde lysosome transport or preventing anterograde movement.. In support of this idea, overexpression of WT-RILP induced lysosome aggregation near the nucleus and ...
We have followed the transfer of EGF-EGF receptor (EGFR) complexes from endosomal vacuoles that contain transferrin receptors (TfR) to lysosome vacuoles identified by their content of HRP loaded as a 15-min pulse 4 h previously. We show that the HRP-loaded lysosomes are lysosomal-associated membrane protein-1 (LAMP-1) positive, mannose-6-phosphate receptor (M6PR) negative. and contain active acid hydrolase. EGF-EGFR complexes are delivered to these lysosomes intact and are then rapidly degraded. Preactivating the HRP contained within the preloaded lysosomes inhibits the delivery of EGFR and degradation of EGF, and results in the accumulation of EGFR-containing multivesicular bodies (MVB). With time these accumulating MVB undergo a series of maturation changes that include the loss of TfR, the continued recruitment of EGFR, and the accumulation of internal vesicles, but they remain LAMP-1 and M6PR negative. The mature MVB are often seen to make direct contact with lysosomes containing ...
Cellular clearance is a fundamental process required by the cells of every species. In eukaryotes, most of the cellular clearing processes occur in a specialized organelle, the lysosome. Given that the requirements of the degradative machinery in a cell may vary depending on tissue type, age and environmental conditions, we postulated that a system coordinates lysosomal activity and that lysosomal function is subject to transcriptional regulation. Using a systems biology-based approach, we discovered a gene regulatory network (CLEAR: Coordinated Lysosomal Enhancement And Regulation) that controls lysosomal biogenesis and function (Sardiello et al, Science 2009) and a master gene, the bHLH-leucine zipper transcription factor TFEB, which binds to CLEAR target sites in the promoter of lysosomal genes and positively regulates their expression (Sardiello et al, Science 2009). TFEB overexpression induces lysosomal biogenesis and increases the cells ability to degrade complex molecules such as mutated ...
The lysosomal acidification defect linked to cytotoxicity of mutations in the P-type ATPase ATP13A2/PARK9 in Parkinsons disease (PD) prompts comparison to the similar mechanism operating in AD due to mutations of presenilin 1. Dehay and colleagues used nearly the same extensive battery of methods as Lee et al. (2010) to evaluate autophagy and lysosomal function in fibroblasts from PD patients and other model cell systems. While the two studies implicate different lysosomal constituents in these two diseases, they reveal pathogenic mechanisms involving defects in lysosome function that are remarkably similar and mutually validating. In both diseases, a lysosomal component needed for acidification is prematurely degraded in the endoplasmic reticulum and fails to reach the lysosome in amounts required for full function. In early onset AD caused by mutations of PS1, the V01a subunit of the proton pump vATPase is improperly chaperoned by the mutant PS1 and is degraded during its exit from the ER, ...
The CE moiety in Ox-LDL is hydrolyzed normally in lysosomes, but the resulting UC is trapped in the lysosomes secondary to the effect of oxysterols that are present in Ox-LDL.5 However, the mechanism responsible for trapping UC in the lysosomes has not been explored. Since SM binds UC with high affinity,18 19 20 21 22 the goal of this study was to examine whether SM accumulates in the macrophage lysosomes following cell incubation with Ox-LDL and whether SM accumulation can be responsible for trapping of the lipoprotein UC in the macrophage lysosomes. The present study indeed showed that Ox-LDL-derived SM accumulates in lysosomes as a result of an impaired SM hydrolysis by the lysosomal SMase. We also demonstrated that 7-KC, the major oxidized cholesterol derivative in Ox-LDL,5 40 41 is a potent inhibitor of macrophage lysosomal SMase. This oxysterol can thus lead to the lysosomal accumulation of Ox-LDL-derived UC secondary to SM accumulation in the macrophage lysosomes.. The mechanisms whereby ...
TY - JOUR. T1 - Intramitochondrial recruitment of endolysosomes mediates Smac degradation and constitutes a novel intrinsic apoptosis antagonizing function of XIAP E3 ligase. AU - Hamacher-Brady, Anne. AU - Choe, S. C.. AU - Krijnse-Locker, J.. AU - Brady, Nathan Ryan. PY - 2014/12/1. Y1 - 2014/12/1. N2 - Intrinsic apoptosis involves BH3-only protein activation of Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP). Consequently, cytochrome c is released from the mitochondria to activate caspases, and Smac (second mitochondria-derived activator of caspases) to inhibit XIAP-mediated caspase suppression. Dysfunctional mitochondria can be targeted for lysosomal degradation via autophagy (mitophagy), or directly through mitochondria-derived vesicle transport. However, the extent of autophagy and lysosomal interactions with apoptotic mitochondria remains largely unknown. We describe here a novel pathway of endolysosomal processing of mitochondria, activated in response to canonical ...
The endolysosomal system and autophagy are essential components of macromolecular turnover in eukaryotic cells. The low-abundance signaling lipid PI(3,5)P2 is a key regulator of this pathway. Analysis of mouse models with defects in PI(3,5)P2 biosynthesis has revealed the unique dependence of the mammalian nervous system on this signaling pathway. This insight led to the discovery of the molecular basis for several human neurological disorders, including Charcot-Marie-Tooth disease and Yunis-Varon syndrome. Spontaneous mutants, conditional knockouts, transgenic lines, and gene-trap alleles of Fig4, Vac14, and Pikfyve (Fab1) in the mouse have provided novel information regarding the role of PI(3,5)P2in vivo. This review summarizes what has been learned from mouse models and highlights the utility of manipulating complex signaling pathways in vivo.
A cells digestive enzymes are enclosed in a membrane bound organelle. How can these molecules funtion in the cell? The KGB Agent answer: This membrane bound organelle is the lysosome that contains an array of enzymes capable of breaking down all types of biological polymers-proteins, nucleic acids, carbohydrates, and lipids. Lysosomes function as the digestive system of the cell, serving both to degrade material taken up from outside the cell and to digest obsolete components of the cell itself. In their simplest form, lysosomes are visualized as dense spherical vacuoles, but they can display considerable variation in size and shape as a result of differences in the materials that have been taken up for digestion. Lysosomes thus represent morphologically diverse organelles defined by the common function of degrading intracellular material. You will find lysosomes in nearly every animal-like eukaryotic cell. Lysosomes hold enzymes that were created by the cell. What creates a lysosome? Youll have
The cytotoxic activity of activated macrophages against tumorigenic target cells appears to be mediated by lysosomal enzymes of activated macrophage origin. Lysosomes of activated macrophages are secreted directly into the cytoplasm of susceptible target cells, which subsequently undergo heterolysis. This reaction can be inhibited by agents which prevent the exocytosis of macrophage lysosomes (hydrocortisone) or which interfere with the action of lysosomal enzymes (trypan blue). ...
Although the pathogenesis of Parkinsons disease (PD) is considered multifactorial, evidence from genetics and cell biology has implicated specific molecular pathways. This article summarizes evidence that suggests that the level of intracellular alpha-synuclein is critical for the onset of neurodegeneration with Lewy bodies and dependent, to a large extent, on lysosomal degradation. The function of other key proteins that emerged from genetics is discussed: Pink1 and Parkin regulate the degradation of damaged mitochondria by the lysosome (mitophagy). Glucocerebrosidase and ATP13A2 are important components of this degradative organelle. VPS35 and LRRK2 may regulate trafficking within lysosome-dependent pathways, such as autophagy and endosomal vesicle recycling. Clinically, diffuse alpha-synucleinopathy or dementia seems to correlate with mutations which interfere with the broader function of lysosomal pathways, whereas a predominantly motor syndrome and nigrostriatal degeneration is associated with
The present experiments demonstrate that, just as for yeast cell-free homotypic vacuole fusion (Peters and Mayer 1998), cell-free heterotypic fusion of mammalian late endosomes and lysosomes requires Ca2+, probably mediating its effects via calmodulin. The Ca2+ is derived from the organelle lumen and is required at a late step in fusion after the requirement for a rab protein.. While the observation that BAPTA inhibits late endosome-lysosome membrane fusion with an IC50 of ∼2 mM, although EGTA has no effect even at 5 mM, is at first sight surprising, it is not without precedent in vertebrate membrane fusion systems. Thus, cell-free nuclear vesicle fusion during nuclear envelope assembly was shown to be inhibited by 5 mM BAPTA but unaffected by 12 mM EGTA (Sullivan et al. 1993). This effect was explained by the fact that at physiological pH, BAPTA exchanges Ca2+ ∼100 times faster than EGTA, reflecting faster rates of association and dissociation. Therefore, facilitated diffusion can cause ...
Lysosomes are small structures inside cells that specialize in breaking down unwanted proteins and other cellular components. These "waste" components could potentially damage or kill the cell. One biochemical process that lysosomes use to accomplish their task is called the autophagic-lysosomal pathway. Malfunction of lysosomes in general, and the autophagic-lysosomal pathway in particular, have been implicated in several neurodegenerative disorders, including Alzheimers disease. Impaired lysosomal function can lead to the overproduction of beta-amyloid from its parent molecule, amyloid precursor protein (APP). Beta-amyloid is a protein fragment closely linked to Alzheimers pathology. Recent studies have found that the production and activities of lysosomes are partly regulated by a transcription factor called TFEB. Transcription factors affect cellular activity by influencing how genes are expressed in the cells. In preliminary experiments, Abhinav Diwan, M.D., and colleagues have observed ...
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The microphthalmia family of transcription factors (MiT/TFEs) controls lysosomal biogenesis and is negatively regulated by the nutrient sensor mTORC1. However, the mechanisms by which cells with constitutive mTORC1 signaling maintain lysosomal catabolism remain to be elucidated. Using the murine epidermis as a model system, we found that epidermal Tsc1 deletion resulted in a phenotype characterized by wavy hair and curly whiskers, and was associated with increased EGFR and HER2 degradation. Unexpectedly, constitutive mTORC1 activation with Tsc1 loss increased lysosomal content via upregulated expression and activity of MiT/TFEs, whereas genetic deletion of Rheb or Rptor or prolonged pharmacologic mTORC1 inactivation had the reverse effect. This paradoxical increase in lysosomal biogenesis by mTORC1 was mediated by feedback inhibition of AKT, and a resulting suppression of AKT-induced MiT/TFE downregulation. Thus, inhibiting hyperactive AKT signaling in the context of mTORC1 loss-of-function ...
Cellular organelles allow the localized regulation of specialized processes. Under certain conditions, such as increased growth, organelles may be required to alter their function. Coordinated regulation of the gene networks required for mitochondrial and endoplasmic reticulum function has been observed. Now, Sardiello et al. (p. 473; published online 25 June) have discovered a gene network regulating the lysosome, the major organelle involved in the degradation of internalized macromolecules. Many lysosomal genes were regulated by a single transcription factor, TFEB. TFEB itself can be activated when the lysosome malfunctions and can regulate both the abundance of lysosomes found in the cell, as well as the ability to degrade complex molecules, including a mutant protein that accumulates in patients with Huntingtons disease. These results may have implications for the treatment of human lysosomal storage disorders, which are characterized by the aberrant accumulation of macromolecules causing ...
In metazoans, lysosomes are characterized by a unique tubular morphology, acidic pH, and specific membrane protein (LAMP) and lipid (cholesterol) composition as well as a soluble protein (hydrolases) composition. Here we show that perturbation to the eye-color gene, light, results in impaired lysosomal acidification, sterol accumulation, altered endosomal morphology as well as compromised lysosomal degradation. We find that Drosophila homologue of Vps41, Light, regulates the fusion of a specific subset of biosynthetic carriers containing characteristic endolysosomal membrane proteins, LAMP1, V0-ATPase and the cholesterol transport protein, NPC1, with the endolysosomal system, and is then required for the morphological progression of the multivesicular endosome. Inhibition of Light results in accumulation of biosynthetic transport intermediates that contain these membrane cargoes, whereas under similar conditions, endosomal delivery of soluble hydrolases, previously shown to be mediated by Dor, ...
Autophagy is of importance in the regulation of cell differentiation and senescence in podocytes, the highly differentiated glomerular epithelial cells. It is possible that derangement of autophagy under different pathological conditions activates or enhances Epithelial-to-Mesenchymal Transition (EMT) in podocytes, resulting in glomerular sclerosis. To test this hypothesis, the present study produced lysosome dysfunction by inhibition of vacuolar- type H+-ATPase (V-ATPase) to test whether deficiency of autophagic flux enhances EMT in podocytes. By Western blot analysis, inhibition of lysosome function by V-ATPase inhibitor or its siRNA was found to induce a significantly enhanced EMT in cultured podocytes, as shown by marked decreases in P-cadherin (P-cad) and zonula occludens-1 (ZO-1) as epithelial markers and simultaneous increases in the mesenchymal markers, fibroblast specific protein-1 (FSP-1) and α-smooth muscle actin (α-SMA). These changes in EMT markers were confirmed by confocal microcopy.
Exploring the mechanism of the drugs cancer-preventing action provided some intriguing insights.. At the doses used in the new study, which were similar to those needed to prevent malaria, chloroquine triggered the death of premalignant cells. This suggests that within the context of MYC overexpression, the drug induces apoptotic cell death-programmed cell death-in response to ineffective autophagic protein degradation and lysosomal changes in the cell. (Lysosomes are cellular recycling centers that degrade old and unwanted material in the cell and recycle building blocks that are used for cell growth.) The p53 protein can induce apoptosis in response to DNA damage or stress, and the studys results suggest that alterations in lysosomal function trigger a p53-dependent cell death response. Our studies have established that chloroquine inhibits a late step in the autophagy pathway by inhibiting lysosome functions that provide necessary material used to keep tumor cells alive under times of ...
By using video microscopy with fluorescent tagging of the two organelles, the scientists observed that the mitochondria and lysosomes formed stable contacts inside living human cells. The authors also employed other advanced imaging techniques - including electron microscopy and super-resolution imaging - to discover that the formation, and subsequent loosening, of these contacts is regulated by a lysosomal protein called RAB7.. "The discovery of these mitochondria-lysosome contacts is extremely exciting," said first author Yvette Wong, PhD, a postdoctoral fellow in Kraincs laboratory. "We now show that these contacts offer a potential site through which mitochondria and lysosomes can crosstalk, and it suggests that defects in the regulation of this contact site may drive the pathogenesis of various human diseases.". In follow-up studies, the scientists are now investigating how dysfunction of the proteins that tether mitochondria and lysosomes together may affect the function of the ...
Synopsis: The realization of new technologies and the development of targeted biopharmaceutical therapies have accelerated in the last decade with over 30 such compounds currently in clinical trials. With ongoing development and evaluation of strategies, such as antibody drug conjugates, to effectively deliver compounds to targeted cell populations through the endocytic-lysosomal pathway, the development and availability of novel reagents will become paramount. Isolated rat hepatic tritosomes and human hepatic lysosomes are in vitro systems that can be utilized to quickly and conveniently evaluate compound stability and guide development direction of biopharmaceutical candidates. In this study, subcellular isolation techniques combined with immunoblotting, protease arrays, and enzymatic activity assays were carried out to characterize isolated rat tritosomes and human hepatic lysosomes ...
The lysosomes are used for the digestion of macromolecules from phagocytosis (ingestion of other dying cells or larger extracellular material), endocytosis (where receptor proteins are recycled from the cell surface), and autophagy (where old or unneeded organelles or proteins, or microbes which have invaded the cytoplasm are delivered to the lysosome). Autophagy may also lead to autophagic cell death, a form of programmed self-destruction, or autolysis, of the cell, which means that the cell is digesting itself. Other functions include digesting foreign bacteria (or other forms of waste) that invade a cell and helping repair damage to the plasma membrane by serving as a membrane patch, sealing the wound. Lysosomes also do much of the cellular digestion required to digest tails of tadpoles and to remove the web from the fingers of a 3-6 month old fetus. This process of programmed cell death is called apoptosis.[1] ...
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Familial Alzheimers disease (FAD) is associated with mutations in the gene encoding presenilin 1 (PS1), a component of the γ-secretase complex, which cleaves type I membrane proteins, such as amyloid precursor protein. Mutations in PS1 are also associated with defects in autophagy in neurons; however, the mechanism involved is unknown. Lee et al. found that autophagy was impaired in blastocysts from PS1 knockout (PS1 KO) mice compared with that in wild-type (WT) blastocysts, which led to the accumulation of autophagic vacuoles (AVs) in PS1 KO cells. Fusion of autophagosomes with lysosomes was normal in PS1 KO cells, but degradation of autolysosomal components was blocked. The pH of lysosomes in PS1 KO cells was higher than that in lysosomes from WT cells, which was associated with the absence of the vacuolar ATPase Voa1 subunit (a proton pump that acidifies lysosomes) from the PS1 KO lysosomes. In WT cells, PS1 associated with Voa1 in the endoplasmic reticulum (ER) and was required for the ...
Within APCs, ubiquitination regulates the trafficking of immune modulators such as MHC class II and CD86 (B7.2) molecules. MARCH1 (membrane-associated RING-CH), a newly identified ubiquitin E3 ligase expressed in APCs, ubiquitinates MHC class II, thereby reducing its surface expression. Following LPS-induced maturation of dendritic cells, MARCH1 mRNA is down-regulated and MHC class II is redistributed to the cell surface from endosomal compartments. Here, we show that MARCH1 expression is also regulated at the posttranscriptional level. In primary dendritic cell and APC cell lines of murine origin, MARCH1 had a half-life of ,30 min. MARCH1 degradation appears to occur partly in lysosomes, since inhibiting lysosomal activity stabilized MARCH1. Similar stabilization was observed when MARCH1-expressing cells were treated with cysteine protease inhibitors. Mutational analyses of MARCH1 defined discrete domains required for destabilization, proper localization, and functional interaction with ...
Cellular Screening Methods for the Study of Nanoparticle- Induced Lysosomal Damage. By Eleonore Fröhlich. Nanoparticles (NPs) are included in many products of daily life and present in the environment. Due to the potential of NPs to improve quality and stability of consumer and health and medical products, it is expected that the exposure of humans to engineered NPs will rather increase than decrease in the future. Although NPs did not act acutely cytotoxic on these concentrations, they may cause adverse effects upon chronic exposure. Cytotoxicity testing in long-term cultures and analysis of organelle function could identify such effects. Cells take up NPs mainly via active mechanisms, and these routes deliver their payload predominantly to lysosomes. Acute exposure of cells to NPs can have adverse effects on lysosome morphology and function, but lysosomes are also potential targets for accumulation. The chapter explains the role of lysosomes and describes techniques for labeling and ...
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How are lysosomal degradation pathways spatially organized in the complex landscape of a neuron? Cheng et al. (2018. J Cell Biol. https://doi.org/10.1083/jcb.201711083) and Yap et ...
There is delayed but increased FA oxidation in 6-week apoB ASO-treated livers. Lipolysis of lipids within autolysosomes, with delivery of their FAs to mitochondria, could lead to oxidation that would compensate for the lack of secretion of VLDL, but our studies of FA oxidation in primary hepatocytes had not demonstrated differences between cells from control ASO- and apoB ASO-treated mice (Figure 2G). We considered the possibility that the 2-hour labeling-collection protocol used for those studies was too short to observe the oxidation of 14C OA which, after incorporation into lipids in the ER membrane, would have to move to the lumen, then be incorporated into autophagosomes that would have to fuse to lysosomes before the lipids could be hydrolyzed to allow released 14C OA to finally be oxidized by mitochondria. This schema is supported by published data demonstrating that the peak fusion of autophagosomes with lysosomes can occur as late as 16 hours after stimulation of autophagy (23, ...
Detail záznamu - The 2,2,4,4,5,5-hexachlorobiphenyl-enhanced degradation of connexin 43 involves both proteasomal and lysosomal activities - Detail záznamu - Knihovna Akademie věd České republiky
Ion-dependent channels and transporters have been identified in lysosomes, including the V-ATPase H+ pump and transient receptor potential mucolipin channels (TRPMLs), the principle Ca2+ release channels in the lysosome, but much less is understood about the roles of Na+ and K+ in lysosomal physiology. Wang et al. describe a voltage-sensitive, Ca2+-activated K+ current in the lysosome (LysoKVCa) and show that LysoKVCa regulates lysosomal membrane potential and refilling of lysosomal Ca2+ stores. ...
Cation channels present in the ES incorporate users with the TRP (transient receptor likely) channel superfamily, specifically TRPML channels (mucolipins) and also two-pore channels (TPCs). In recent reports, these channels are located to Enjoy vital roles in endolysosomal trafficking, lysosomal exocytosis, and autophagy. Mutation or reduction of those channel proteins can impact several endolysosomal trafficking pathways. A task for TPCs in cancer cell migration and metastasis, connected to distinctive defects in endolysosomal trafficking for example integrin trafficking, has actually been not long ago set up. With this evaluate, we give an summary to the operate of lysosomes in cancer with a selected deal with the roles which TPCs and TRPML channels Enjoy from the ES And the way This may affect cancer cells. Full ...
While both snapin‐S50D and snapin‐L99K mutants induced SV accumulation at presynaptic boutons (Fig 3A and B) by disrupting the retrograde transport of SV cargoes along the endolysosomal pathway (Fig 2B and C), only snapin‐L99K reduced the releasable pool size (Fig 5A-C). In view of the biochemical data (Supplementary Fig S3A), this raises the possibility that dysbindin/BLOC‐1‐dependent function (Route 2) is required for maintaining the releasable pool size. Our previous study revealed desynchronized EPSCs in snapin−/− neuronal cultures (Pan et al, 2009), reminiscent of manipulations that decrease the physical coupling of SVs with voltage‐dependent Ca2+ channels (Mochida et al, 1996). Such deficits can be readily rescued by raising the extracellular Ca2+ concentration [Ca2+]ext (Pan et al, 2009). Therefore, snapin represents an attractive candidate in facilitating the positional priming of SVs toward Ca2+ entry sites (Wadel et al, 2007), thus influencing the Ca2+ sensitivity of ...
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.
Association of hVam6p with clusters of lysosomes and late endosomes. HeLa cells were transiently transfected with HA-hVam6p and processed for immunoelectron m
TY - JOUR. T1 - Carbohydrate Processing Enzyme of the Lysosome: Diseases Caused by Missfolded Mutants and Sugar Mimetics as Correcting Pharmacological Chaperones. AU - Stütz, Arnold. AU - Wrodnigg, Tanja. PY - 2016. Y1 - 2016. M3 - Article. VL - 73. SP - 225. EP - 302. JO - Advances in Carbohydrate Chemistry and Biochemistry. JF - Advances in Carbohydrate Chemistry and Biochemistry. SN - 0065-2318. ER - ...
Lysosomes and MVBs in the bnch mutant visual system. (A-D) TEM sections through bnch mutant eyes. (A) Multilammellar onion-like structure with morphologically