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β2-adrenergic agonists rescue lysosome acidification and function in PSEN1 deficiency by reversing defective ER to lysosome delivery of ClC-7

ABSTRACT: Lysosomal dysfunction is considered pathogenic in Alzheimer Disease (AD). Loss of Presenilin-1(PSEN1) function causing early onset AD impedes acidification via defective vATPase V0a1 subunit delivery to lysosomes. We report that isoproterenol and related β2-adrenergic agonists re-acidify lysosomes in PSEN1 KO cells and fibroblasts from PSEN1 familial AD(FAD) patients, restores lysosomal calcium homeostasis and proteolysis, and reverses impaired autophagy flux. We identify a novel rescue mechanism involving PKA-mediated facilitated delivery of ClC-7 to lysosomes, which stimulates chloride influx and reverses markedly lowered Cl- content of PSEN1 KO lysosomes. Notably, PSEN1 loss-of-function impedes ER-to-lysosome delivery of ClC-7, thus accounting for lysosomal Cl- deficits that compound pH deficits due to deficient vATPase function. Transcriptomics of PSEN1-deficient cells reveal strongly down-regulated ER-to-lysosome transport pathways and reversibility by isoproterenol. Our findings uncover a broadened PSEN1 role in lysosomal ion homeostasis and novel pH modulation of lysosomes through β-adrenergic regulation of ClC-7, which can be therapeutically modulated.

ORGANISM(S): Mus musculus

PROVIDER: GSE136894 | GEO | 2020/02/29

REPOSITORIES: GEO

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β2-adrenergic agonists rescue lysosome acidification and function in PSEN1 deficiency by reversing defective ER to lysosome delivery of ClC-7

Project description:β2-adrenergic agonists rescue lysosome acidification and function in PSEN1 deficiency by reversing defective ER to lysosome delivery of ClC-7

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Enhanced and selective translation expands the lysosome size and promotes antigen presentation during phagocyte activation

Project description:The mechanisms that govern organelle remodeling remain poorly defined. Lysosomes degrade cargo from various routes including endocytosis, phagocytosis and autophagy. For phagocytes, lysosomes are a kingpin organelle since they are essential to kill pathogens and process and present antigens. During phagocyte activation, lysosomes undergo a striking reorganization, changing from dozens of globular structures to a tubular network, in a process that requires the phosphatidylinositol-3-kinase-AKT-mTOR signalling pathway. Here, we show that lysosomes undergo a remarkable expansion in volume and holding capacity during phagocyte activation within 2 h of LPS stimulation. Lysosome expansion was paralleled by an increase in lysosomal protein levels, but this was unexpectedly independent of TFEB and TFE3 transcription factors, known to scale up lysosome biogenesis. Instead, we demonstrate a hitherto unappreciated mechanism of acute organelle expansion via mTORC1-dependent increase in translation of mRNAs encoding key lysosomal proteins. Importantly, mTORC1-dependent increase in translation activity was necessary for efficient and rapid antigen presentation by dendritic cells. Collectively, we identified a previously unknown and functionally relevant mechanism for lysosome expansion that relies on mTORC1-dependent enhanced translation of mRNAs to boost protein synthesis and lysosome biogenesis in response to an infection signal.

2020-01-07 | GSE136470 | GEO

Peripheral positioning of lysosomes supports melanoma aggressiveness

Project description:Emerging evidences suggest that both function and position of organelles are pivotal for tumor cell dissemination. Among them, lysosomes stand out as they integrate metabolic sensing with gene regulation and secretion of proteases. Yet, how lysosomes function is linked to their position and thereby control metastatic progression remains elusive. Here, we analyzed lysosome subcellular distribution in micropatterned patient-derived melanoma cells and found that lysosome spreading scales with their aggressiveness. Peripheral lysosomes promote invadopodia-based matrix degradation and invasion of melanoma cells which is directly linked to their lysosomal and cell transcriptional programs. When controlling lysosomal positioning using chemo-genetical heterodimerization in melanoma cells, we demonstrated that perinuclear clustering impairs lysosomal secretion, matrix degradation and invasion. Impairing lysosomal spreading in a zebrafish metastasis model significantly reduces invasive outgrowth. Our study provides a mechanistic demonstration that lysosomal positioning controls cell invasion, illustrating the importance of organelle adaptation in carcinogenesis.

2023-07-31 | E-MTAB-13165 | biostudies-arrayexpress

NPC1 regulates the distribution of phosphatidylinositol 4 kinases at Golgi and Lysosome membranes

Project description:Cholesterol and phosphoinositides (PI) are two critically important lipids that are found in cellular membranes and dysregulated in many disorders. Therefore, uncovering molecular pathways connecting these essential lipids may offer new therapeutic insights. We report that loss of function of lysosomal Niemann-Pick Type C1 (NPC1) cholesterol transporter, which leads to neurodegenerative NPC disease, initiates a signaling cascade that alters the cholesterol/phosphatidylinositol 4-phosphate (PtdIns4P) countertransport cycle between Golgi-endoplasmic reticulum (ER), as well as lysosome-ER membrane contact sites (MCS). Central to these disruptions is increased recruitment of phosphatidylinositol 4-kinases-PI4KIIα and PI4KIIIβ-which boosts PtdIns4P metabolism at Golgi and lysosomal membranes. Aberrantly increased PtdIns4P levels elevate constitutive anterograde secretion from the Golgi complex, and mTORC1 recruitment to lysosomes. NPC1 disease mutations phenocopy the transporter loss of function and can be rescued by inhibition or knockdown of either key phosphoinositide enzymes or their recruiting partners. In summary, we show that the lysosomal NPC1 cholesterol transporter tunes the molecular content of Golgi and lysosome MCS to regulate intracellular trafficking and growth signaling in health and disease.

2021-09-15 | MTBLS2612 | MetaboLights

Lysosomal dysfunction in Down syndrome is APP-dependent and mediated by APP-βCTF (C99)

Project description:Lysosomal failure underlies pathogenesis of numerous congenital neurodegenerative disorders and is an early and progressive feature of Alzheimer’s disease (AD) pathogenesis. Here, we report that lysosomal dysfunction in Down Syndrome (Trisomy 21) requires the extra gene copy of amyloid precursor protein (APP) and is mediated by the beta cleaved carboxy terminal fragment of APP (APP-βCTF, C99). In primary fibroblasts from individuals with Down Syndrome (DS), lysosomal degradation of autophagic and endocytic substrates is selectively impaired causing them to accumulate in enlarged autolysosomes/lysosomes. Direct measurements of lysosomal pH uncovered a significant elevation (0.6 units) associated with slowed LC3 turnover and the inactivation of cathepsin D (CTSD) and other lysosomal hydrolases known to be unstable or less active when lysosomal pH is persistently elevated. RNA sequencing analysis excluded a transcriptional contribution to hydrolase declines. Normalizing lysosome pH by delivering acidic nanoparticles to lysosomes ameliorated lysosomal deficits, implicating pH elevation as their primary basis. Cortical neurons cultured from the Ts2 mouse model of DS exhibited lysosomal deficits similar to those in DS cells. Lowering APP expression with siRNA or BACE1 inhibition reversed cathepsin deficits in both fibroblasts and neurons. Deleting one BACE1 allele from adult Ts2 mice had similar rescue effects in vivo. The modest elevation of endogenous APP-βCTF needed to disrupt lysosomal function in DS is relevant to sporadic AD where APP-βCTF, but not APP, is also elevated. Our results extend evidence that impaired lysosomal acidification drives progressive lysosomal failure in multiple forms of AD.

2019-05-30 | GSE127880 | GEO

A Lysosome membrane regeneration pathway depends on TBC1D15 and autophagic lysosomal reformation proteins

Project description:Acute lysosomal membrane damage reduces the cellular population of functional lysosomes. However, these damaged lysosomes have a remarkable recovery potential independent of lysosomal biogenesis and remain unaffected in TFEB/TFE3-depleted cells. We combined proximity labelling based proteomics, biochemistry and high-resolution microscopy to unravel a new lysosomal membrane regeneration pathway which is dependent on ATG8, lysosomal membrane protein LIMP2, the Rab7 GAP TBC1D15, and proteins required for autophagic lysosomal reformation (ALR) including Dynamin2, Kinesin5B and Clathrin. Upon lysosomal damage, LIMP2 act as a lysophagy receptor to bind ATG8, which in turn recruits TBC1D15 to damaged membranes. TBC1D15 hydrolyses Rab7-GTP to segregate the damaged lysosomal mass and provides a scaffold to assemble and stabilize the ALR machinery, potentiating the formation of lysosomal tubulesand subsequent Dynamin2-dependent scission. TBC1D15-mediated lysosome regeneration was also observed in a cell culture model of oxalate nephropathy.

2023-03-07 | PXD040191 | Pride

A quantitative proteomic profile revealed the crucial roles of lysosome in the microbial infection

Project description:Lysosome played vital roles for both innate and adaptive immunity. It has been widely accepted that lysosome functioned more than a digestive organelle. However, it was still largely unknown for the proteome changes of lysosome on various microbes, and the understanding of lysosomal proteome from the purified lysosome is another obstacle that needs to be resolved. Here, we performed a proteomic study on the enriched lysosomes from THP1 cells after infected by Listeria monocytogenes (L. m), Herpes Simplex Virus 1 (HSV-1) and Vesicular Stomatitis Virus (VSV). Combining with the GO analysis, we identified 284 lysosomal related proteins from the totally identified 4560 proteins. We also constructed the protein-protein interaction networks for the changed proteins and revealed the core lysosomal proteins in responding for diverse microbial infections. From this study, we not only revealed that lysosome responded in a different manner for the bacterial or virus infection, but also proposed a new way for the proteome research for the enriched organelles.

2017-05-04 | PXD005748 | Pride

Astaburuaga2019 - ODE model of lysosomal ion homeostasis (LIH) including calcium pathways

Project description:To investigate the putative differential effect of chloride transport on lysosomal ion homeostasis,we generated an ODE mathematical model for this system. Our mathematical model builds upon a previously published model for lysosomal homeostasis (Grabe et al. 2001 J. Gen. Physiol, Ishida et al. 2013 J. Gen. Physiol), and further includes the (de)activation kinetics of the ClC-7 antiporter and Ca2+ uptake/release mechanisms. Our new model tracks the total number of ions within the lysosomal lumen over time. It considers different types of lysosomal ion channels and exchangers and two possible lysosomal Ca2+ transporters. The variation in the total number of each ion within the lysosome is described by an ordinary differential equation (ODE), and the rate of change is determined by the flux of the corresponding ion across the lysosomal membrane. The model considers different elements affecting lysosomal ion homeostasis, among which are: (i) the V-ATPase pump, (ii) a proton leak, (iii) the luminal proton buffering capacity, (iv) ClC-7 chloride/proton exchanger, (v) Ca2+ /proton exchanger (CAX), (vi) passive channels for K+ , Na+ , and Ca2+ , and (vii) Donnan particles, which are negatively charged particles or molecules trapped in the lysosomal lumen. It allows for the simulation of different scenarios mimicking the differential transport of chloride, its impact on Ca2+ uptake and release and ultimately on lysosomal homeostasis. We provide a Supplementary Information file (Astaburuaga et al. Cells 2019) with the full description of the mathematical model. The equations written in purple were newly developed, the other elements were retrieved from a previous mathematical model as indicated above.

2019-10-22 | MODEL1910220001 | BioModels

Endocytosed dsRNAs induce lysosomal membrane permeabilization that allows cytosolic dsRNA translocation for Drosophila RNAi response

Project description:RNA interference (RNAi) is a gene-silencing mechanism triggered by the cytosolic entry of double-stranded RNAs (dsRNAs). Many animal cells internalize extracellular dsRNAs via endocytosis for RNAi induction. However, it is not clear how the endocytosed dsRNAs are translocated into the cytosol across the endo/lysosomal membrane. Herein, we show that in Drosophila S2 cells, endocytosed dsRNAs induce lysosomal membrane permeabilization (LMP) that allows cytosolic dsRNA translocation. LMP mediated by dsRNAs requires the lysosomal Cl−/H+ antiporter ClC-b/DmOstm1. In clc-b or dmostm1 knockout S2 cells, extracellular dsRNAs are endocytosed and reach the lysosomes normally but fail to enter the cytosol. Pharmacological induction of LMP restores extracellular dsRNA-directed RNAi in clc-b or dmostm1-knockout cells. Furthermore, clc-b or dmostm1 mutant flies are defective in extracellular dsRNA-directed RNAi and its associated antiviral immunity. Therefore, endocytosed dsRNAs have an intrinsic ability to induce ClC-b/DmOstm1-dependent LMP that allows cytosolic dsRNA translocation for RNAi responses in Drosophila cells.

2024-07-07 | GSE244523 | GEO

Multi cell line comparison of lysosome enriched fractions reveals cell type specific features and novel lysosomal proteins

Project description:Lysosomes are the main degradative organelles of mammalian cells and are responsible for the breakdown of the majority of cellular macromolecules and the recycling of their building blocks. To accomplish this task, lysosomes contain ~60 hydrolases. Malfunction of these proteins, as well as other proteins responsible for the transport of small molecules or proteins, lead to the accumulation of their respective substrates. This accumulation of substrates results in heavy impairment of lysosomal function leading to ~70 lysosomal storage disorders (LSDs). A better understanding of lysosomal composition is of high importance not only for a better understanding of LSDs, but also for cellular function. Analysis of lysosomes by mass spectrometry-based proteomics presents an attractive approach to allow for a better characterization of lysosomes. In the current study, we investigated the lysosomal proteome from six different cell lines (HEK293, HeLa, HuH-7, SH-SY5Y, MEF and NIH3T3) by lysosome enrichment using SPIONs (superparamagnetic iron oxide nanoparticles) combined with mass spectrometry-based proteomics. Comparison of the individual proteomes revealed cell type specific characteristics in lysosomal protein expression. To allow for the discrimination of lysosomal from unspecific enriched proteins, we included a differentially SILAC (stable isotope labelling by amino acids in cell culture) labelled control sample. Afterwards, lysosomal proteins were identified using a bimodal distribution model. By combination of data from several cell lines, we were able to generate a high confidence list of putative novel lysosomal proteins of which several were confirmed by immunostaining.

2023-02-21 | PXD020600 | Pride

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