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Multiomic Approach Characterises the Neuroprotective Role of Retromer in Regulating Lysosomal Health

ABSTRACT: Retromer controls cellular homeostasis through regulating integral membrane protein sorting and transport and by controlling maturation of the endo-lysosomal network. Retromer dysfunction, which is linked to neurodegenerative disorders including Parkinson’s and Alzheimer’s diseases, manifests in complex cellular phenotypes, though the precise nature of this dysfunction, and its relation to neurodegeneration, remain unclear. Here, we perform the first integrated multiomics approach to provide precise insight into the impact of Retromer dysfunction on endo-lysosomal health and homeostasis within a human neuroglioma cell model. We quantify profound changes to the lysosomal proteome, indicative of broad lysosomal dysfunction and inefficient autophagic lysosome reformation, coupled with a reconfigured cell surface proteome and secretome reflective of increased lysosomal exocytosis. Through this global proteomic approach and parallel transcriptomic analysis, we provide an unprecedented integrated view of Retromer function in regulating lysosomal homeostasis and emphasise its role in neuroprotection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE223292 | GEO | 2023/04/17

REPOSITORIES: GEO

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Multiomic Approach Characterises the Neuroprotective Role of Retromer in Regulating Lysosomal Health

Project description:Retromer controls cellular homeostasis through regulating integral membrane protein sorting and transport and by controlling late-stage maturation of the endo-lysosomal network. Retromer dysfunction, which is linked to neurodegenerative disorders including Parkinson’s and Alzheimer’s diseases, manifests in complex cellular phenotypes, though the precise nature of this dysfunction, and its relation to neurodegeneration, remain unclear. Here, we perform the first integrated multiomics approach to provide precise insight into the impact of Retromer dysfunction on endo-lysosomal health and homeostasis within a human neuroglioma cell model. We quantify profound changes to the lysosomal proteome, indicative of broad lysosomal dysfunction and inefficient autophagic lysosome reformation, coupled with a reconfigured cell surface proteome and secretome reflective of increased lysosomal exocytosis. Through this global proteomic approach and parallel transcriptomic analysis, we provide an unprecedented integrated view of Retromer function in regulating lysosomal homeostasis and emphasise its role in neuroprotection.

2023-07-20 | PXD041323 | Pride

Epidermal Stratification Requires Retromer-Mediated Desmoglein-1 Recycling

Project description:Sorting transmembrane cargo is essential for tissue development and homeostasis. However, mechanisms of intracellular trafficking in stratified epidermis are poorly understood. Here we identify an interaction between the retromer endosomal trafficking component, VPS35, and the desmosomal cadherin, Desmoglein-1 (Dsg1). Dsg1 is specifically expressed in stratified epidermis and when properly localized on the plasma membrane of basal keratinocytes, promotes stratification. We show that the retromer drives Dsg1 recycling from the endo-lysosomal system to the plasma membrane to support stratification. The retromer-enhancing chaperone, R55, promotes the membrane localization of Dsg1 and a trafficking-deficient mutant associated with a severe inflammatory skin disorder, enhancing its ability to promote stratification. In the absence of Dsg1, retromer association with and expression of the glucose transporter GLUT1 increases, exposing a potential link between Dsg1 deficiency and epidermal metabolism. Our work provides the first evidence for retromer function in epidermal regeneration, identifying it as a potential therapeutic target.

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An engineered trafficking biosensor reveals a role for DNAJC13 in DOR downregulation

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Multiomic Approach Characterises the Neuroprotective Role of Retromer in Regulating Lysosomal Health

Project description:Multiomic Approach Characterises the Neuroprotective Role of Retromer in Regulating Lysosomal Health

| PRJNA925533 | ENA

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

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ESCRT-I controls lysosomal membrane protein homeostasis and restricts MCOLN1-dependent TFEB/TFE3 signaling.

Project description:Within the endolysosomal pathway in mammalian cells, ESCRT complexes facilitate degradation of membrane proteins from limiting membranes of late endosomes. Recent studies revealed that yeast ESCRT proteins also sort for degradation, ubiquitinated proteins from vacuolar membrane. However, whether mammalian ESCRTs perform similar function at lysosomes remained unknown. Here, we studied the involvement of mammalian ESCRT-I in maintaining lysosomal membrane homeostasis and its implication in lysosome-related signaling. We show that ESCRT-I restricts the size of lysosomes and promotes degradation of lysosomal Ca2+ channel, MCOLN1 protein. ESCRT-I depletion induced transcriptional response related to MiT-TFE signaling and cholesterol biosynthesis, pointing to lysosomal dysfunction. The lack of ESCRT-I promoted abnormal cholesterol accumulation on lysosomes and activated TFEB/TFE3 transcription factors in Ca2+-MCOLN1-dependent, but lipid-independent manner. Hence, our study provides evidence that ESCRT-I maintains lysosomal homeostasis and elucidates MiT-TFE regulatory mechanism activated in response to ESCRT-I deprivation

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