Transcriptomic data of downregulated chaperone-mediated autophagy in glioma stem cell activity.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE181556 | GEO | 2021/08/11
REPOSITORIES: GEO
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Project description:Chaperone-mediated autophagy (CMA) is a homeostatic process essential for the lysosomal degradation of individual proteins. CMA activity directly depends on the levels of LAMP2A, critical receptor at the lysosomal membrane, to which CMA substrate proteins are bound. In glioblastoma (GBM), the most common and aggressive brain cancer in the adulthood, high levels of LAMP2A have been linked to TMZ resistance and tumor-associated pericytes. However, the implication of LAMP2A, and hence CMA, in glioblastoma stem cells (GSCs) remains unknown. In this work, we show that LAMP2A expression is enriched in patient-derived GSC population and its knock-down diminishes GSCs tumorigenic activities. Proteomic and transcriptomic analysis of LAMP2A knocked-down GSCs revealed reduced extracellular matrix (ECM) interaction effectors in both analyses. Moreover, immune system and mitochondrial metabolism related pathways were remarkably deregulated at proteome level, whereas PI3K-AKT and p53 pathways were altered in RNAseq study. Moreover, clinical samples of GBM tissue presented overexpression of LAMP2 and its high levels correlated with advanced glioma grade and poor overall survival. In conclusion, we identified a novel role of CMA directly regulating GSCs activity via multiple pathways at proteome and transcriptome level.
2023-03-11 | PXD027069 | Pride
Project description:Chaperone-mediated autophagy (CMA) is a homeostatic process essential for the lysosomal degradation of individual proteins. CMA activity directly depends on the levels of LAMP2A, critical receptor at the lysosomal membrane, to which CMA substrate proteins are bound. In glioblastoma (GBM), the most common and aggressive brain cancer in the adulthood, high levels of LAMP2A have been linked to TMZ resistance and tumor-associated pericytes. However, the implication of LAMP2A, and hence CMA, in glioblastoma stem cells (GSCs) remains unknown. In this work, we show that LAMP2A expression is enriched in patient-derived GSC population and its knock-down diminishes GSCs tumorigenic activities. Proteomic and transcriptomic analysis of LAMP2A knocked-down GSCs revealed reduced extracellular matrix (ECM) interaction effectors in both analyses. Moreover, immune system and mitochondrial metabolism related pathways were remarkably deregulated at proteome level, whereas PI3K-AKT and p53 pathways were altered in RNAseq study. Moreover, clinical samples of GBM tissue presented overexpression of LAMP2 and its high levels correlated with advanced glioma grade and poor overall survival. In conclusion, we identified a novel role of CMA directly regulating GSCs activity via multiple pathways at proteome and transcriptome level.
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Project description:Transcriptomic data of downregulated chaperone-mediated autophagy in glioma stem cell activity.
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Project description:The most common genetic risk factors for Parkinson’s disease (PD) are a set of heterozygous mutant (MT) alleles of the GBA1 gene that encodes -glucocerebrosidase (GCase), an enzyme that is normally trafficked from the endoplasmic reticulum and Golgi apparatus to the lysosomal lumen. We examined isolated lysosomes from anterior cingulate cortex, a region of high alpha-synuclein accumulation in GBA-PD, and found that while lysosomal GCase is entirely luminal in healthy controls, half of the lysosomal GBA-PD GCase was present on the lysosomal surface. This lysosomal mislocalization is dependent on a pentapeptide motif in GCase used for targeting of cytosolic proteins to lysosomes for degradation by chaperone-mediated autophagy (CMA), a type of autophagy inhibited by PD-related pathogenic proteins including -synuclein and LRRK2. Single cell transcriptional analysis and comparative proteomics of brains from GBA-PD patients demonstrated reduced CMA activity and overall proteome changes similar to those observed in mouse models with CMA blockage. We found that the delivery of unfolded mutant GCase to lysosomes decreased CMA due to recognition of unfolded mutant GCase to the chaperone hsc70, and the resulting complex binds the CMA receptor LAMP2A at the lysosomal surface. Unfolded mutant GCase is a poor substrate for translocation into the lysosomal lumen, and by interfering with LAMP2A multimerization, blocks the translocation and causes cytosolic accumulation of other CMA substrates including -synuclein and tau. In primary substantia nigra dopamine neurons, MT GCase led to neuronal death, while loss of the GCase CMA motif or deletion of -synuclein rescued the neurons. These results indicate how MT GCase alleles may converge with other PD proteins to block CMA function and produce -synuclein accumulation.
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Project description:Chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI) are pathways for selective degradation of cytosolic proteins in endo-lysosomal compartments. These autophagic processes share as a first step the recognition of the same five amino acid motif in substrate proteins by the hsc70 chaperone, therefore raising the possibility of a regulatory network linking the two pathways. In this work, we demonstrate the existence of a compensatory relationship between CMA and eMI and identify a role for the chaperone protein Bag6 in triage and internalization of eMI substrates into the late endosome. Association and dynamics of Bag6 at the late endosome membrane change during starvation which we found that, contrary to other autophagic pathways, causes a decline in eMI activity. Collectively, we establish a coordinated function of eMI with CMA, identify the interchangeable subproteome degraded by these pathways and start to elucidate the molecular mechanisms that facilitate the switch between them.
2023-10-30 | PXD029580 | Pride
Project description:Previous studies suggest that the reduction of SMAD3 (mothers against decapentaplegic homolog 3) has a great impact on tumor development, but its exact pathological function remains unclear. In this study, we found that the protein level of SMAD3 was greatly reduced in human-grade IV glioblastoma tissues, in which LAMP2A (lysosome-associated membrane protein type 2A) was significantly up-regulated. LAMP2A is a key rate-limiting protein of chaperone-mediated autophagy (CMA), a lysosome pathway of protein degradation that is activated in glioma. We carefully analyzed the amino-acid sequence of SMAD3 and found that it contained a pentapeptide motif biochemically related to KFERQ, which has been proposed to be a targeting sequence for CMA. In vitro, we confirmed that SMAD3 was degraded in either serum-free or KFERQ motif deleted condition, which was regulated by LAMP2A and interacted with HSC70 (heat shock cognate 71 kDa protein). Using isolated lysosomes, amino-acid residues 75 and 128 of SMAD3 were found to be of importance for this process, which affected the CMA pathway in which SMAD3 was involved. Similarly, down-regulating SMAD3 or up-regulating LAMP2A in cultured glioma cells enhanced their proliferation and invasion. Taken together, these results suggest that excessive activation of CMA regulates glioma cell growth by promoting the degradation of SMAD3. Therefore, targeting the SMAD3-LAMP2A-mediated CMA-lysosome pathway may be a promising approach in anti-cancer therapy.
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Project description:The activity of chaperone-mediated autophagy (CMA), a catabolic pathway for selective degradation of cytosolic proteins in lysosomes, decreases with age, but the consequences of this functional decline in vivo remain unknown. In this work, we have generated a conditional knockout mouse to selectively block CMA in liver. We have found that blockage of CMA causes hepatic glycogen depletion and hepatosteatosis. The liver phenotype is accompanied by reduced peripheral adiposity, increased energy expenditure, and altered glucose homeostasis. Comparative lysosomal proteomics revealed that key enzymes in carbohydrate and lipid metabolism are normally degraded by CMA and that impairment of this regulated degradation contributes to the metabolic abnormalities observed in CMA-defective animals. These findings highlight the involvement of CMA in regulating hepatic metabolism and suggest that the age-related decline in CMA may have a negative impact on the energetic balance of old organisms.
2014-12-31 | GSE49553 | GEO
Project description:Chaperone-mediated autophagy (CMA) is a homeostatic process essential for the lysosomal degradation of a selected subset of the proteome. CMA activity directly depends on the levels of LAMP2A, a critical receptor for CMA substrate proteins at the lysosomal membrane. In glioblastoma (GBM), the most common and aggressive brain cancer in adulthood, high levels of LAMP2A in the tumor and tumor-associated pericytes have been linked to temozolomide resistance and tumor progression. However, the role of LAMP2A, and hence CMA, in any cancer stem cell type or in glioblastoma stem cells (GSC) remains unknown. In this work, we show that LAMP2A expression is enriched in patient-derived GSCs, and its depletion diminishes GSC-mediated tumorigenic activities. Conversely, overexpression of LAMP2A facilitates the acquisition of GSC properties. Proteomic and transcriptomic analysis of LAMP2A-depleted GSCs revealed reduced extracellular matrix interaction effectors in both analyses. Moreover, pathways related to mitochondrial metabolism and the immune system were differentially deregulated at the proteome level. Furthermore, clinical samples of GBM tissue presented overexpression of LAMP2, which correlated with advanced glioma grade and poor overall survival. In conclusion, we identified a novel role of CMA in directly regulating GSCs activity via multiple pathways at the proteome and transcriptome levels.SignificanceA receptor of chaperone-mediated autophagy regulates glioblastoma stem cells and may serve as a potential biomarker for advanced tumor grade and poor survival in this disease.
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Project description:Inhibition of Histone H3-H4 Chaperone Pathways Rescues Dysfunctional Oncohistone H2B
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Project description:The most common genetic risk factors for Parkinson’s disease (PD) are a set of heterozygous mutant (MT) alleles of the GBA1 gene that encodes Beta-glucocerebrosidase (GCase), an enzyme normally trafficked through the ER/ Golgi apparatus to the lysosomal lumen. We found that half of the GCase in lysosomes from post-mortem human GBA-PD brains was present on the lysosomal surface, and that this mislocalization depends on a pentapeptide motif in GCase used to target cytosolic protein for degradation by chaperone-mediated autophagy (CMA). Unfolded mutant GCase at the lysosomal surface inhibits CMA, causing accumulation of CMA substrates including -synuclein. Using single cell transcriptional analysis and comparative proteomics of brains from GBA-PD patients we confirmed reduced CMA activity and proteome changes comparable to those in CMA-deficient mouse brain. Loss of the MT GCase CMA motif is sufficient to rescue primary substantia nigra dopamine neurons from MT-GCase induced neuronal death. We conclude that MT GCase alleles block CMA function and produce -synuclein accumulation.
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