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Identification of host regulators of Mycobacterium tuberculosis phenotypic states uncovers a role for the MMGT1-GPR156-lipid droplet axis in the induction of persistence [AR_SNR_RNAseq]

ABSTRACT: The ability of Mycobacterium tuberculosis (Mtb) to establish latency directly impacts disease and response to treatment but the host’s influence on this switch remains elusive. Using a novel Mtb reporter strain to separate macrophages infected with replicating or latent Mtb, we performed transcriptomics and genome-wide CRISPR screens. After validating the recovery of known susceptibility loci from TB GWAS as modifiers of active replication, we identified multiple pathways and novel modulators of latency. We validated multiple controllers of latency and mechanistically characterized the transporter MMGT1. MMGT1-deficient macrophages upregulated lipid metabolism genes and accumulated lipid droplets during infection. Critically, targeting triacylglycerol synthesis reduced both droplet formation and Mtb latency. We identified GPR156, an orphan GPCR as a key inducer of droplet accumulation in ΔMMGT1 cells. Altogether, our work uncovers the role of MMGT1-GPR156-lipid droplets in the induction of Mtb latency, suggesting that host-directed therapies could be used to modulate Mtb phenotypes during infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210687 | GEO | 2023/06/01

REPOSITORIES: GEO

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Identification of host regulators of Mycobacterium tuberculosis phenotypic states uncovers a role for the MMGT1-GPR156-lipid droplet axis in the induction of persistence [THP1_MMGT1_RNAseq]

Project description:The ability of Mycobacterium tuberculosis (Mtb) to establish latency directly impacts disease and response to treatment but the host’s influence on this switch remains elusive. Using a novel Mtb reporter strain to separate macrophages infected with replicating or latent Mtb, we performed transcriptomics and genome-wide CRISPR screens. After validating the recovery of known susceptibility loci from TB GWAS as modifiers of active replication, we identified multiple pathways and novel modulators of latency. We validated multiple controllers of latency and mechanistically characterized the transporter MMGT1. MMGT1-deficient macrophages upregulated lipid metabolism genes and accumulated lipid droplets during infection. Critically, targeting triacylglycerol synthesis reduced both droplet formation and Mtb latency. We identified GPR156, an orphan GPCR as a key inducer of droplet accumulation in ΔMMGT1 cells. Altogether, our work uncovers the role of MMGT1-GPR156-lipid droplets in the induction of Mtb latency, suggesting that host-directed therapies could be used to modulate Mtb phenotypes during infection.

2023-06-01 | GSE210690 | GEO

Identification of host regulators of Mycobacterium tuberculosis phenotypic states uncovers a role for the MMGT1-GPR156-lipid droplet axis in the induction of persistence [CRISPRscreen]

2023-06-01 | GSE210689 | GEO

Lipid droplet proteomics of THP1 macrophages infected with Mycobacterium tuberculosis

Project description:Growing evidence suggests the importance of lipid metabolism in pathogenesis of tuberculosis. Neutral lipids form the majority of lipids in caseous granulomas characteristic of tuberculosis. Macrophage lipid droplets form the store house of these lipids, yet infection induced changes in the proteome of these dynamic organelles remains elusive. Here we employed quantitative proteomics to identify alterations induced upon infection with live Mycobacterium tuberculosis in comparison with heat killed bacilli and uninfected macrophages. Association of specific proteins coupled with lysosomal function was found to be increased upon infection with live M. tuberculosis. Biochemical and microscopy based evidence validated the enrichment of the small GTPase Arl8b, the guanine nucleotide effector LAMTOR1, and the scavenger receptor SCARB2 on lipid droplets during live Mtb infection. We validated the localization of Arl8b on lipid droplets using super-resolution microscopy. Increased abundance of these lysosomal proteins on lipid droplets upon infection with live Mtb suggests active manipulation of the host lipid droplets by the pathogen. Furthermore, depletion of lipid droplets upon stable knockdown of diacylglycerol O-acyltransferase led to reduction in lysosomal acidification of infected cells, suggesting an active role of lipid droplets in lysosomal function during infection.

2019-11-14 | PXD008950 | Pride

The lipid droplet protein DHRS3 is a regulator of melanoma cell state

Project description:Lipid droplets are fat storage organelles composed of a protein envelope and a lipid rich core. Dynamic regulation of this protein envelope underlies differential lipid droplet formation and function in diverse cell types. In melanoma, the ability to form lipid droplets has been linked to tumor progression and metastasis, but it is not known whether lipid droplet proteins play a role in these phenotypes. To address this, we performed proteomic analysis of the lipid droplet envelope in melanoma. We found that proteins expressed in the lipid droplet were differentially enriched in distinct melanoma states, ranging from melanocytic to neural crest like. DHRS3, which is involved in the conversion of all-trans-retinal to all-trans-retinol, is significantly upregulated in the MITFLO/neural crest-like melanoma cell state, and markedly reduced in the MITFHI/melanocytic state. Increased DHRS3 expression is sufficient to drive the MITFHI/melanocytic cells to a more undifferentiated and invasive state. These changes are due to retinoic acid mediated regulation of melanocytic genes through the retinoid X receptors (RXR). Our data demonstrate that melanoma cell state can be regulated by expression of lipid droplet proteins which affect downstream retinoid signaling.

2024-03-25 | GSE262095 | GEO

Diet-MEF2 Interactions Shape Lipid Droplet Diversification in Muscle to Influence Drosophila Lifespan

Project description:The number, size, and composition of lipid droplets can be influenced by dietary changes that shift energy substrate availability. This diversification of lipid droplets can promote metabolic flexibility and shape cellular stress responses in unique tissues with distinctive metabolic roles. Using Drosophila, we uncovered a role for myocyte enhancer-factor 2 (MEF2) in modulating diet-dependent lipid droplet diversification within adult striated muscle, impacting mortality rates. Muscle-specific attenuation of MEF2, whose chronic activation maintains glucose and mitochondrial homeostasis, leads to the accumulation of large, cholesterol ester-enriched intramuscular lipid droplets in response to high calorie, carbohydrate sufficient diets. The diet-dependent accumulation of these lipid droplets also correlates with both enhanced stress protection in muscle and increases in organismal lifespan. Furthermore, MEF2 attenuation releases an antagonistic regulation of cell cycle gene expression programs, and up-regulation of Cyclin E is required for diet-and-MEF2 dependent diversification of intramuscular lipid droplets. The integration of MEF2-regulated gene expression networks with dietary responses thus plays a critical role in shaping muscle metabolism and function, further influencing organismal lifespan. Together, these results highlight a potential protective role for intramuscular lipid droplets during dietary adaptation.

2020-08-11 | GSE147676 | GEO

Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy

Project description:Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα on tau pathology are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolic processes, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.

2023-07-12 | GSE236875 | GEO

Saturated fatty acids promotes β-cell toxicity by disabling intracellular lipid droplet formation through S-acylation of FIT2

Project description:Palm and coconut oils are linked to cardiovascular disease and diabetes because of their high saturated fatty acid (SFA) content but exactly how exogenous SFAs, but not unsaturated fatty acids (UFA), are toxic to cells remains unknown. In insulin-producing, β-cells of the Islets of Langerhans, loss of which exacerbates diabetes, we found that SFAs but not UFAs were toxic because they disable a highly conserved lipid droplet biogenesis machinery. We show that palmitate (a major SFA of these oils), but not palmitoleic or oleic, S-acylates the highly conserved ER-resident FITM2 protein, required for lipid coalescence and droplet budding from the ER. The S-acylation marks FITM2 for ubiquitination and proteosomal degradation, leaving SFAs within the ER instead safe sequestration within lipid droplets. ER-stress ensues with rapid induction of ER stress leading to β-cell apoptosis. Specific deletion of FITM2 in β-cells disrupts calcium signaling and key β-cell TFs and exacerbates high fat diet-induced ER stress and diabetes. Rescue by overexpression ameliorates ER-stress and β-cell apoptosis thus demonstrating an important link between lipid species and cell ability to sequester them away from the ER in the form of lipid droplets.

2021-07-08 | GSE133939 | GEO

Altered hepatic lipid droplet morphology and lipid metabolism in fasted Plin2 null mice

Project description:Perilipin 2 (Plin2) binds to the surface of hepatic lipid droplets (LDs) with expression levels that correlate with triacylglyceride (TAG) content. We investigated if Plin2 is important for hepatic LD storage in fasted or high-fat diet-induced obese Plin2+/+ and Plin2-/- mice. Plin2-/- mice had comparable body weights, metabolic phenotype, glucose tolerance, and circulating TAG and total cholesterol levels compared to Plin2+/+ mice, regardless of the dietary regime. Both fasted and high-fat fed Plin2-/- mice stored reduced levels of hepatic TAG compared to Plin2+/+ mice. Fasted Plin2-/- mice stored fewer, but larger hepatic lipid droplets compared to Plin2+/+ mice. Detailed hepatic lipid analysis showed substantial reductions in accumulated TAG species in fasted Plin2-/- mice compared to Plin2+/+ mice, whereas cholesteryl esters and phosphatidylcholines were increased. RNA sequencing revealed minor differences in hepatic gene expression between fed Plin2+/+ and Plin2-/- mice, in contrast to marked differences in gene expression between fasted Plin2+/+ and Plin2-/- mice. Our findings demonstrate that Plin2 is required to regulate hepatic lipid droplet size and storage of neutral lipid species in the fasted state, while its role in obesity-induced steatosis is less clear.

2023-10-13 | GSE214064 | GEO

Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy

Project description:Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα deletion in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deficient enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.

2023-08-09 | PXD043877 | Pride

Calsyntenin-3b constrains lipid droplet expansion to promote a multilocular adipocyte phenotype and thermogenesis

Project description:Multilocular adipocytes are a hallmark of thermogenic adipose tissue, but the factors that enforce this cellular phenotype are unknown. Here, we show that an adipocyte-specific product of the Clstn3 locus (CLSTN3b) present only in placental mammals facilitates the rapid utilization of stored triglyceride by limiting lipid droplet (LD) size. CLSTN3b is an integral ER protein that localizes to ER-LD contact sites via a conserved hairpin domain. Mice lacking CLSTN3b have altered LD morphology and increased lipid accumulation in BAT, as well as heightened sensitivity to cold challenge, despite having no defect in adrenergic signaling. Conversely, forced expression of CLSTN3b promotes a multilocular LD phenotype in cultured cells and BAT and facilitates triglyceride utilization. Mechanistically, CLSTN3b associates with CIDE proteins and impairs their ability to transfer lipid between droplets, thereby limiting LD expansion. These findings define a molecular mechanism that maximizes LD surface area to facilitate lipid utilization in thermogenic adipocytes.

2022-10-07 | GSE181123 | GEO

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