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GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway

ABSTRACT: GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway

PROVIDER: PRJNA861993 | ENA |

REPOSITORIES: ENA

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Analysis of intact mannose-6-phosphate glycopeptides

Project description:We have repurposed standard phosphoproteomics workflow based on Fe3+IMAC for enrichment ofmannose-6-phosphate modified glycopeptides. This worklfow was used to profile lysosomal acid hydrolases in HeLa and CHO cell lines. We have combined this approach with CRISPR/Cas9 KO of acid phosphatases 2 and 5 responsible for dephosphorylation of mannose-6-phosphate glycopeptides in the lysosome. This combined approach enabled significantly deeper coverage of CHO mannose-6-phosphate glycoproteome.

2018-12-18 | PXD010333 | Pride

GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway.

Project description:The mannose-6-phosphate (M6P) biosynthetic pathway for lysosome biogenesis has been studied for decades and is considered a well-understood topic. However, whether this pathway is regulated remains an open question. In a genome-wide CRISPR/Cas9 knockout screen, we discover TMEM251 as the first regulator of the M6P modification. Deleting TMEM251 causes mistargeting of most lysosomal enzymes due to their loss of M6P modification and accumulation of numerous undigested materials. We further demonstrate that TMEM251 localizes to the Golgi and is required for the cleavage and activity of GNPT, the enzyme that catalyzes M6P modification. In zebrafish, TMEM251 deletion leads to severe developmental defects including heart edema and skeletal dysplasia, which phenocopies Mucolipidosis Type II. Our discovery provides a mechanism for the newly discovered human disease caused by TMEM251 mutations. We name TMEM251 as GNPTAB cleavage and activity factor (GCAF) and its related disease as Mucolipidosis Type V.

| S-EPMC9468337 | biostudies-literature

GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway

Project description:To investigate the expression profilings after knocking out TMEM251. We then performed gene expression profiling analysis using data obtained from RNA-seq of 3 different TMEM251 sgRNA knockout cells compared to WT

2022-07-28 | GSE209652 | GEO

Phosphosugar stress in Bacillus subtilis: Intracellular accumulation of mannose 6-phosphate derepresed the glcR-phoC operon from repression by GlcR

Project description:Bacillus subtilis phosphorylates sugars during or after their transport into the cell.Perturbation in the conversion of intracellular phosphosugars to the central carbon metabolitesand accumulation of phosphosugars can impose stress on the cells. In this study, we investigated the effect of phosphosugar stress on B. subtilis. Preliminary experiments indicated that the non-matabolizable analogs of glucose were unable to impose stress on B. subtilis. In contrast, deletion of manA encoding mannose 6-phosphate isomerase (responsible for conversion of mannose 6-phosphate to fructose 6-phosphate) resulted in growth arrest and bulged cell shape in the medium containing mannose. Besides, an operon encoding a repressor (GlcR) and a haloic acid dehalogenase (HAD)-like phosphatase (PhoC; previously YwpJ) were upregulated. Integration of the PglcR-lacZ cassette into different mutational backgrounds indicated that PglcR is induced when (i) a manA-deficient strain is cultured with mannose or (ii) when glcR is deleted.GlcR represses the transcription of glcR-phoC bybinding to the A-type core elements of PglcR. Electrophoretic mobility shift assay showed no interaction between mannose 6-phosphate (or other phosphosugars) and the GlcR-PglcR DNA complex. PhoCwas an acid phosphatase mainly able to dephosphorylate glycerol 3-phosphate and ribose 5- phosphate. Mannose 6-phosphatewas only weakly dephosphorylated by PhoC. Since deletion of glcR and phoCalone or in combination had no effect on the cell duringphosphosugar stress,it is assumed that the derepression of glcR-phoC is a side effect of phosphosugar stress in B. subtilis.

2019-03-13 | GSE128187 | GEO

Reduction of Nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration

Project description:Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding TDP-43, account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS (fALS)-causing mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer’s disease, and Parkinson’s disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a novel function of Nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and lifespan deficits in two distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared along the autophagy-lysosome axis, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.

2023-06-24 | GSE235312 | GEO

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Project description:This is the raw data and Byonic search results of mouse kidney Mannose-6-Phosphate glycoproteome.

2020-03-11 | PXD012402 | Pride

Mouse Liver Mannose-6-Phosphate Glycoproteome LC-MSMS

Project description:This is the raw data and Byonic search results of mouse liver Mannose-6-Phosphate glycoproteome.

2020-03-11 | PXD012404 | Pride

Mouse Lung Mannose-6-Phosphate Glycoproteome LC-MSMS

Project description:This is the raw data and Byonic search results of mouse mouse lung Mannose-6-Phosphate glycoproteome.

2020-03-11 | PXD012403 | Pride

Mouse Heart Mannose-6-Phosphate Glycoproteome LC-MSMS

Project description:This is the raw data and Byonic search results of mouse mouse brain Mannose-6-Phosphate glycoproteome.

2020-03-11 | PXD012401 | Pride

Mouse Brain Mannose-6-Phosphate Glycoproteome LC-MSMS

Project description:This is the raw data and Byonic search results of mouse mouse brain Mannose-6-Phosphate glycoproteome.

2020-03-11 | PXD012400 | Pride

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