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Essential role of MFSD1-GLMP-GIMAP5 in lymphocyte survival and liver homeostasis

ABSTRACT: In this study, we detected three alleles that caused lymphopenia, splenomegaly, progressive liver pathology and extramedullary hematopoiesis (EMH), resulting from N-ethyl-N-nitrosourea (ENU)-induced mutations in the major facilitator superfamily domain containing 1 protein (Mfsd1) which encodes a lysosomal membrane-bound solute carrier protein with no previously described function in immunity. By proteomic analysis, we identified MFSD1 functions together with GLMP (glycosylated lysosomal membrane protein), and GIMAP5 (GTPase of immunity-associated protein 5). Germ line knock alleles of MFSD1, GLMP, and GIMAP5 were generated in mice and confirmed occurrence of lymphopenia, liver pathology, EMH, and lipid deposition in the bone marrow and liver of each strain. We found that the interaction of MFSD1 and GLMP with GIMAP5 is essential to maintain normal GIMAP5 expression that is critical to support lymphocyte development and liver homeostasis that suppresses EMH. These findings provide new insight into the mechanism of how MFSD1-GLMP-GIMAP5 complex functions together to regulate immunity and liver homeostasis that were previously unknown.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive HF

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Jin Huk Choi

PROVIDER: MSV000092540 | MassIVE | Thu Jul 27 11:52:00 BST 2023

REPOSITORIES: MassIVE

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Essential role of MFSD1-GLMP-GIMAP5 in lymphocyte survival and liver homeostasis

Project description:In this study, we detected three alleles that caused lymphopenia, splenomegaly, progressive liver pathology and extramedullary hematopoiesis (EMH), resulting from N-ethyl-N-nitrosourea (ENU)-induced mutations in the major facilitator superfamily domain containing 1 protein (Mfsd1) which encodes a lysosomal membrane-bound solute carrier protein with no previously described function in immunity. By proteomic analysis, we identified MFSD1 functions together with GLMP (glycosylated lysosomal membrane protein), and GIMAP5 (GTPase of immunity-associated protein 5). Germ line knock alleles of MFSD1, GLMP, and GIMAP5 were generated in mice and confirmed occurrence of lymphopenia, liver pathology, EMH, and lipid deposition in the bone marrow and liver of each strain. We found that the interaction of MFSD1 and GLMP with GIMAP5 is essential to maintain normal GIMAP5 expression that is critical to support lymphocyte development and liver homeostasis that suppresses EMH. These findings provide new insight into the mechanism of how MFSD1-GLMP-GIMAP5 complex functions together to regulate immunity and liver homeostasis that were previously unknown.

2023-07-27 | MSV000092538 | MassIVE

Analysis of effects of TM4SF5 deficiency in inguinal white adipose tissue

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Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

Project description:Aneuploidy and aging are correlated; however, a causal link between these two phenomena has remained elusive. Here we show that yeast disomic for a single native yeast chromosome generally have a decreased replicative lifespan. In addition, the extent of this lifespan deficit correlates with the size of the extra chromosome. We identified a mutation in BUL1 that rescues both the lifespan deficit and a protein trafficking defect in yeast disomic for chromosome 5. Bul1 is an E4 ubiquitin ligase adaptor involved in a protein quality-control pathway that targets membrane proteins for endocytosis and destruction in the lysosomal vacuole thereby maintaining protein homeostasis. Concurrent suppression of the aging and trafficking phenotypes suggests that disrupted membrane protein homeostasis in aneuploid yeast may contribute to their accelerated aging. The data reported here demonstrate that aneuploidy can impair protein homeostasis, shorten lifespan, and may contribute to age-associated phenotypes. These are all CGH arrays comparing DNA content between the indicated strain of interest and a wt control.

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

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

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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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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 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.

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Transcription profiling of human EBV transformed cell lines established from patients with a novel immunodeficiency syndrome

Project description:Lysosome-related organelles have versatile functions including protein and lipid degradation, signal transduction, and protein secretion. The molecular elucidation of rare congenital diseases affecting endosomal/lysosomal biogenesis has given insights into physiological functions of the innate and adaptive immune system.. Here, we describe a novel human primary immunodeficiency disorder and provide evidence that the endosomal adaptor protein p14, previously characterized as confining mitogen-activated-protein-kinase (MAPK) signaling to late endosomes, is critical for the function of neutrophils, B-cells, cytotoxic T-cells and melanocytes. Combining genetic linkage studies and transcriptional profiling analysis, we identified a homozygous point mutation in the 3â UTR of p14 (also known as MAPBPIP), resulting in decreased protein expression. In p14-deficient cells, the distribution of late endosomes was severely perturbed, suggesting a novel role for p14 in endosomal biogenesis. These findings have implications for understanding endosomal membrane dynamics, compartmentalization of cell signal cascades, and their role in immunity. Experiment Overall Design: EBV-transformed B cell lines from 2 parents and 2 affected children

2008-06-14 | E-GEOD-6322 | biostudies-arrayexpress

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

Impairment of lipid homeostasis causes lysosomal accumulation of endogenous protein aggregates through ESCRT disruption

Project description:Protein aggregation increases during aging and is a pathological hallmark of many age-related diseases. Protein homeostasis (proteostasis) depends on a core network of factors directly influencing protein production, folding, trafficking, and degradation. Cellular proteostasis also depends on the overall composition of the proteome and numerous environmental variables. Modulating this cellular proteostasis state can influence the stability of multiple endogenous proteins, yet the factors contributing to this state remain incompletely characterized. Here, we performed genome-wide CRISPRi screens to elucidate the modulators of proteostasis state in mammalian cells, using a fluorescent dye to monitor endogenous protein aggregation. These screens recovered components of the known proteostasis network, and uncovered a link between protein and lipid homeostasis. We showed that increased lipid uptake and/or disrupted lipid metabolism led to increased lysosomal, detergent-insoluble protein aggregates and, concomitantly, accumulation of sphingomyelins and cholesterol esters. Proteomic analysis of lysosomes revealed ESCRT accumulation at the lysosomes, suggesting disruption of ESCRT disassembly, lysosomal membrane repair, and microautophagy. Lipid dysregulation leads to lysosomal membrane permeabilization, but does not otherwise impact fundamental aspects of lysosomal and proteasomal functions. Together, these results demonstrate that lipid dysregulation impairs proteostasis via ESCRT disruption, potentially as a result of modified membrane properties.

2024-12-20 | PXD054648 | Pride

Genome-wide analyses in neuronal cells reveal that USF transcription factors regulate lysosomal gene expression [ChIP-chip]

Project description:The upstream stimulating factors (USFs) USF1 and USF2 are ubiquitously expressed transcription factors characterized by a conserved basic helix-loop-helix leucine zipper DNA-binding domain. They form homo- or heterodimers and recognize E-box motifs to modulate gene expression. They are known to regulate diverse cellular functions including the cell cycle, immune response and glucose-lipid metabolism, but their roles in neuronal cells remain to be clarified. Here, we performed chromatin immunoprecipitation of USF1 from mouse brain cortex preparations. Subsequent promoter array analysis (ChIP-chip) indicated that USF1 exclusively bound to the CACGTG E-box motifs in the proximal promoter regions. Importantly, functional annotation of the USF1-binding targets revealed an enrichment of genes related to lysosomal functions. Gene expression arrays using a neuronal cell line subsequently revealed that knockdown of USFs deregulated lysosomal gene expression. Altered expression was validated by quantitative RT-PCR, supporting the conclusion that USFs regulate lysosomal gene expression. Furthermore, USFs knockdown slightly increased LysoTracker staining, implying a role for USFs in modulating lysosomal homeostasis. Together, our comprehensive, genome-scale analyses identified lysosomal genes as targets of USFs in neuronal cells, suggesting a potential additional pathway of lysosomal regulation. ChIP-chip analysis of USF1 and NF-Y in mouse brain cortex. To identify downstream targets of USF1 and NF-Y in neuronal cells, they were chromatin-immunoprecipitated from mouse brain cortical lysates. The obtained chromatin DNAs were labeled with biotin and hybridized on Affymetrix Mouse Promoter 1.0R Array.

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