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GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics

ABSTRACT: During autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The origin and identity of the membranes that form the autophagosome remain to be fully characterized. Here, we investigated the role of cholesterol in starvation-induced autophagy and identify a role for the ER-localized cholesterol transport protein GRAMD1C in the regulation of autophagy and mitochondrial function. We demonstrate that cholesterol depletion leads to a rapid induction of autophagy and a corresponding increased abundance of curved autophagy membranes. We further show that GRAMD1C is a negative regulator of starvation-induced autophagy. Similar to its yeast orthologue, GRAMD1C is recruited to mitochondria through its GRAM domain. Additionally, we find that GRAMD1C depletion leads to increased mitochondrial cholesterol accumulation and mitochondrial oxidative phosphorylation. Finally, we demonstrate that expression of GRAM family genes is linked to clear cell renal carcinoma survival, highlighting the pathophysiological relevance of cholesterol transport proteins.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Tuula Nyman

LAB HEAD: Tuula Nyman

PROVIDER: PXD033125 | Pride | 2022-10-19

REPOSITORIES: Pride

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: GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics through ER-Mitochondria cholesterol transport

Project description:During autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The origin and identity of the membranes that form the autophagosome remain to be fully characterized. Here, we investigated the role of cholesterol in starvation-induced autophagy and identify a role for the ER-localized cholesterol transport protein GRAMD1C in the regulation of autophagy and mitochondrial function. We demonstrate that cholesterol depletion leads to a rapid induction of autophagy, possibly caused by a corresponding increased abundance of curved autophagy membranes. We further show that GRAMD1C is a negative regulator of starvation-induced autophagy. Similar to its yeast orthologue, GRAMD1C is recruited to mitochondria through its GRAM domain. Additionally, we find that GRAMD1C depletion leads to increased mitochondrial cholesterol accumulation and mitochondrial oxidative phosphorylation. Finally, we demonstrate that expression of GRAM family genes is linked to clear cell renal carcinoma survival, highlighting the pathophysiological relevance of cholesterol transport proteins.

2022-10-19 | PXD027502 | Pride

Cholesterol depletion increases expression of autophagy-related genes in mink lung Mv1Lu cells

Project description:Purpose: Employ next generation sequencing (NGS) to study the transcriptomic response to prolonged reduction in the cholesterol level, with emphasis on autophagy-related genes. Methods: Mv1Lu cells were subjected (or not; control) to cholesterol depletion (16 h, with lovastatin and mevalonate in the presence of lipoprotein deficient serum (LPDS), resulting in 30% reduction in the level of free cholesterol). mRNA profiles were generated by deep sequencing, in triplicates, using Illumina NextSeq500. See methods and protocols for details regarding downstream bioinformatic analysis. Results: Using an optimized data analysis workflow sequencing data from lung samples and identified that cholesterol depletion resulted in 2844 and 2822 genes with significantly increased or reduced expression, respectively. The set of differentially expressed genes was significantly enriched with functional annotations relating to cholesterol metabolic regulation and autophagy. These results were correlated with the upregulation of autophagy in biochemical studies. Conclusions: Mild reduction in the cholesterol level leads to a highly significant increase in the expression of multiple autophagy-related genes. The autophagy genes whose expression was modified by cholesterol depletion were scattered onto multiple steps of the autophagy process, and suggested a mainly positive regulation of autophagy by statin treatment.

2021-11-03 | GSE179869 | GEO

mRNA expression data from keratinocytes with disorganized lipid raft structures (by cholesterol depletion by methyl-beta-cyclodextrin)

Project description:Lipid rafts are cholesterol-rich cell signaling platforms and their physiological role can be explored by cholesterol depletion. To dress a global picture of transcriptional changes ongoing after lipid raft disruption, we performed whole-genome expression profiling in epidermal keratinocytes, a cell type which synthesizes its cholesterol in situ. We used microarrays to identify transcriptional changes in gene expression of cholesterol-depleted keratinocytes. Cholesterol depletion by methyl-beta-cyclodextrin disrupts the organization of lipid rafts, which are cholesterol- and sphingolipid-rich membrane microdomains. Transcript levels were measured in autocrine confluent cultures of normal human epidermal keratinocytes were either left untreated (Ctrl), cholesterol-depleted for 1h with 7.5mM methyl-beta-cyclodextrin (MBCD), or mock cholesterol-depleted for 1h with 7.5mM cholesterol-charged methyl-beta-cyclodextrin complexes (MBCD/chol) (Mock cholesterol depletion is a suppementary negative control as this treatment does not extract cholesterol from cell membranes). Samples are analysed either immediately after the treatment (R0h) or after recovery times of 1h (R1h) respectively 8h (R8h). in total 9 samples are analysed and no replicates are performed.

2010-04-17 | E-GEOD-21364 | biostudies-arrayexpress

siRNA of human MCF10A eIF4GI depleted cells vs. controls links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy

Project description:Translation initiation factors have complex functions in cells which are not yet understood. We show that depletion of initiation factor eIF4GI only modestly reduces overall protein synthesis in cells, but phenocopies nutrient-starvation or inhibition of protein kinase mTOR, a key nutrient sensor. eIF4GI depletion impairs cell proliferation, bioenergetics and mitochondrial activity, thereby promoting autophagy. Translation of mRNAs involved in cell growth, proliferation and bioenergetics were selectively inhibited by reduction of eIF4GI, whereas mRNAs encoding proliferation inhibitors and catabolic pathway factors were increased. Depletion or over-expression of other eIF4G family members did not recapitulate these results. The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance. These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy and release tumor cells from control by nutrient sensing. Global regulation of transcription and polysomal association in eIF4GI-silenced cells. Experiment Overall Design: Two sets of experiments are presented. First, overall transcriptome changes were determined for control or eIF4GI silenced cells. Next, mRNAs associated with polysomes were compared between control and eIF4GI silenced cells.

2008-06-11 | E-GEOD-11011 | biostudies-arrayexpress

IFRD1 promotes tumor cells “low-cost” survival under glutamine starvation via inhibiting histone H1.0 nucleophagy

Project description:Glutamine addiction represents a metabolic vulnerability of cancer cells although effective therapeutic targeting of the pathways involved remains to be realized. Here, we disclose the critical role of IFRD1 (interferon-related developmental regulator 1) in the adaptive survival of hepatocellular carcinoma cells (HCC) during glutamine starvation. The induction and translocation of IFRD1 to the endoplasmic reticulum inhibits autophagy by promoting proteasomal degradation of the key autophagy regulator ATG14 in a TRIM21-dependent manner. On the contrary, enforced IFRD1 loss increases autophagy flux leading to cell death. This effect is largely realized through the autophagy-dependent degradation of histone H1.0 causing globally enhanced chromatin accessibility associated with unchecked increases in ribosome and protein biosynthesis . This in turn leads to metabolic exhaustion and death under glutamine starvation. Practically, IFRD1 depletion in preclinical HCC models potentiates glutamine limiting strategies including synergizing with the glutaminase-1 selective inhibitor CB-839. Thus, IFRD1 supports the adaptive survival of cancer cells under glutamine starvation, with potential as a therapeutic target in anti-cancer applications.

2024-03-23 | GSE217406 | GEO

Sugar turns benefit of cholesterol into immune evasion in Helicobacter pylori infected C57BL/6 mice

Project description:Following the initial demonstration of Helicobacter pyloriâ??s pathogenic potential, evidence has been accumulated that H. pylori is the leading cause of gastric ulcers, carcinoma and lymphoma3. Cholesterol is a physiological constituent of membranes critical for their biophysical properties, but is stigmatised as mediating detrimental effects in obesity and cardiovascular disease. Since H. pylori is auxotrophic for cholesterol, we explored the assimilation of cholesterol by H. pylori upon infection. Here we show that H. pylori follows a cholesterol gradient and extracts the lipid from plasma membranes of epithelial cells for subsequent glycosylation. Cholesterol promotes phagocytosis of H. pylori by antigen-presenting cells such as macrophages and dendritic cells and enhances antigen-specific T cell responses. Consistently, cholesterol-rich diet during bacterial challenge leads to a reduction of the H. pylori burden in the stomach. Intrinsic a-glycosylation of cholesterol abrogates phagocytosis of H. pylori and subsequent T cell activation. Hence, we propose a novel mechanism regulating host-pathogen interaction which describes glycosylation of a lipid tipping the scales towards immune evasion or response. color-swap dye-reversal hybridizations

2010-06-30 | E-GEOD-3878 | biostudies-arrayexpress

Deletions in the ATAD3 gene cluster cause cerebellar developmental defects with mitochondrial DNA abnormalities owing to local cholesterol insufficiency

Project description:The DNA in mitochondria is associated with the inner of two membranes and it co-fractionates with the limited amount of cholesterol in the organelles. However, the effects of mitochondrial cholesterol deficiency are largely unknown, and mitochondrial disorders relating to this area of cell metabolism have not been reported hitherto. Using detailed SNP array analysis we have identified patients with impaired cerebellar development and neurological dysfunction who have large deletions in the locus encoding the ATAD3A, ATAD3B and ATAD3C genes. Patient cells with inherited ATAD3 defects display aberrant mitochondrial DNA organization and synthesis associated with disrupted cholesterol metabolism. Moreover drug-induced perturbations of cholesterol metabolism cause mitochondrial DNA disorganization in control cells. The interdependence of mitochondria and cholesterol homeostasis is further corroborated by the presence of mitochondrial DNA aggregation in the genetic cholesterol trafficking disorder Niemann Pick type C disease. Thus, we conclude, mitochondria are fully integrated in the circuitry of cellular cholesterol homeostasis, in which ATAD3 plays a critical role, and the dual problem of perturbed cholesterol homeostasis and mitochndrila dysfunction may be widespread in neurological and neurodegenerative diseases.

2017-06-23 | GSE86550 | GEO

Epigenetic and transcriptional regulation of starvation-induced atrophy and autophagy programs by Foxk1 and Sin3A

Project description:Autophagy is the primary catabolic process triggered in response to starvation. Although autophagic regulation within the cytosolic compartment is well established, it is becoming clear that nuclear events also regulate the induction or repression of autophagy. Nevertheless, a thorough understanding of the mechanisms by which sequence-specific transcription factors modulate expression of genes required for autophagy is lacking. Here, we identify Foxk proteins (Foxk1 and Foxk2) as transcriptional repressors of autophagy in muscle cells and fibroblasts. Interestingly, Foxk1/2 serve to counter-balance another forkhead transcription factor, Foxo3, which induces an overlapping set of autophagic and atrophic targets in muscle. Foxk1/2 specifically recruits Sin3A-HDAC complexes to restrict acetylation of histone H4 and expression of critical autophagy genes. Remarkably, mTOR promotes the transcriptional activity of Foxk1 by facilitating nuclear entry to specifically limit basal levels of autophagy in nutrient-rich conditions. Our study highlights an ancient, conserved mechanism whereby nutritional status is interpreted by mTOR to restrict autophagy by repressing essential autophagy genes via Foxk-Sin3-mediated transcriptional control. Examination of (1) chromatin binding of Foxk1 and Sin3A in non-starved myoblasts and (2) gene expression profiling upon either starvation or siRNA-mediated depletion of Foxk1 relative to a non-starved control.

2014-11-17 | E-GEOD-56932 | biostudies-arrayexpress

The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα

Project description:The class 3 phosphoinositide 3-kinase (PI3K) is required for the lysosomal degradation by autophagy and vesicular trafficking, assuring adaptation to energy shortages. Mitochondrial lipid catabolism is another important energy source. Autophagy and mitochondrial metabolism are transcriptionally controlled by nutrient sensing nuclear receptors. However, it is not known whether the class 3 PI3K contributes to this regulation. Here we show that hepatocyte-specific inactivation of Vps15, the essential regulatory subunit of the class 3 PI3K, results in mitochondrial depletion and a failure to oxidize fatty acids. Mechanistically, the transcriptional activity of Peroxisome Proliferator Activated Receptor alpha (PPARα), a nuclear receptor that orchestrates fatty acid catabolism, is blunted in Vps15-deficient livers. We find PPARα transcriptional repressors Histone Deacetylase 3 (Hdac3) and Nuclear receptor co-repressor 1 (NCoR1) accumulated in Vps15-deficient livers due to defective autophagic flux. Pharmacologic activation of PPARα with a synthetic ligand, re-expression of its co-activator Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC-1α) or inhibition of Hdac3 restored mitochondrial biogenesis and lipid oxidation in Vps15-deficient hepatocytes. These findings reveal a role for the class 3 PI3K and autophagy in transcriptional coordination of mitochondrial metabolism.

2020-02-06 | E-MTAB-7685 | biostudies-arrayexpress

eIF4GI Links Nutrient Sensing by mTOR to Cell Proliferation and Inhibition of Autophagy

2008-04-01 | GSE11011 | GEO

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