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Cavin1 Deficiency Alters Lung macrophage homeostasis in Mouse

ABSTRACT: Caveolae are cell membrane invaginations that are highly abundant in adipose tissue, endothelial cells and lung and are present at lower levels in other tissues. The formation of caveolae is dependent of the expression of various structural proteins that serve as scaffolding for these membrane invaginations. Cavin1 is a newly identified structural protein whose deficiency leads to absence of caveolae formation and to the development of a lipodystrophic phenotype. In this study we show Cavin1 expression is critical for regulating macrophage number and gene-expression (phenotype) in the lung. We used microarrays to detail the global programme of gene expression in alveolar macrophage in a Cavin1 knock-out mouse and identified distinct classes of dysregulated genes during this process.

ORGANISM(S): Mus musculus

PROVIDER: GSE42169 | GEO | 2013/06/07

SECONDARY ACCESSION(S): PRJNA179225

REPOSITORIES: GEO

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Cavin1 Deficiency Alters Lung macrophage homeostasis in Mouse

Project description:Caveolae are cell membrane invaginations that are highly abundant in adipose tissue, endothelial cells and lung and are present at lower levels in other tissues. The formation of caveolae is dependent of the expression of various structural proteins that serve as scaffolding for these membrane invaginations. Cavin1 is a newly identified structural protein whose deficiency leads to absence of caveolae formation and to the development of a lipodystrophic phenotype. In this study we show Cavin1 expression is critical for regulating macrophage number and gene-expression (phenotype) in the lung. We used microarrays to detail the global programme of gene expression in alveolar macrophage in a Cavin1 knock-out mouse and identified distinct classes of dysregulated genes during this process. Bronchoalveolar Lavage performed though a 22-gauge needle tied in place to trachea with PBS containing 0.5 mM ethylenediaminetetraacetic acid (EDTA). Aliquots of 0.5 to 1 ml were instilled into the lungs under direct observation to ensure that all segments of lung were inflated, and aspirated back into the syringe. This was repeated five times per mouse. RNA was extracted from extracted alveolar macrophages and hybridized to Affymetrix microarrays for gene expression analysis.

2013-06-07 | E-GEOD-42169 | biostudies-arrayexpress

Identification of Cavin3-interacting proteins

Project description:Caveolae are specialized domains of the plasma membrane. Formation of these invaginations is dependent on the expression of Caveolin-1 or -3 and proteins of the cavin family. In response to stress, caveolae disassemble and cavins are released from caveolae, allowing cavins to potentially interact with intracellular targets. Here, we describe the intracellular (non-plasma membrane) cavin interactome using biotin affinity proteomics and mass spectrometry. We validate 47 potential cavin-interactor proteins using a cell-free expression system and protein-protein binding assays. These data, together with pathway analyses, revealed novel roles for cavin proteins in metabolism and stress signaling. We validated the interaction between one candidate interactor protein, protein phosphatase 1 alpha (PP1α), and Cavin-1 and -3 and show that UV treatment causes release of Cavin3 from caveolae allowing interaction with, and inhibition of, PP1α. This interaction increases H2AX phosphorylation to stimulate apoptosis, identifying a pro-apoptotic signaling pathway from surface caveolae to the nucleus.

2019-07-23 | PXD014081 | Pride

Identification of Cavin3 interacting proteins

2019-07-23 | PXD014094 | Pride

Knocking down CAVIN1 in WPMY-1 normal prostate stromal cells

Project description:Lipid uptake occurs through caveolae, plasma membrane invaginations formed by caveolins (CAV) and caveolae-associated protein 1 (CAVIN1). Genetic alterations of CAV1N1 and CAV1 modify lipid metabolism and underpin lipodystrophy syndromes. Lipids contribute to tumorigenesis by providing fuel to cancer metabolism and supporting growth and signaling. Tumor stroma supports tumor proliferation, invasion and metastasis but how stromal lipids influence these processes remain to be defined. Here we show that stromal CAVIN1 regulates lipid abundance in the prostate cancer microenvironment and suppresses metastasis. We show that depletion of CAVIN1 in prostate stromal cells markedly reduces their lipid droplet accumulation and increases inflammation.

2022-01-19 | GSE146229 | GEO

Role of Caveolin 1 in metabolic programming of fetal brain

Project description:Caveolae are plasma membrane invaginations found in most cells of mammals. Caveolin-1 (Cav1) encodes a major protein of the lipid rafts of these membrane structures. Cav1-null mice, though viable, show various phenotypic defects. At an early adult age, these mice show brain aging that resemble brain of one and half year old wildtype mice, and exhibit symptoms that are hallmarks of Alzheimer’s disease. It is not known if the ablation of Cav1 in these mice impacts the brain at the fetal stage that then influences brain function later in life. Single nuclei RNA sequencing was performed with fetal brain of wildtype and Cav1 knockout mice. Results showed that specific metabolism genes were differentially expressed bewteen different glial cells.

2023-09-20 | GSE214759 | GEO

Role of Caveolin 1 in metabolic programming of fetal brain (bulk RNA-seq data)

Project description:Caveolae are plasma membrane invaginations found in most cells of mammals. Caveolin-1 (Cav1) encodes a major protein of the lipid rafts of these membrane structures. Cav1-null mice, though viable, show various phenotypic defects. At an early adult age, these mice show brain aging that resemble brain of one and half year old wildtype mice, and exhibit symptoms that are hallmarks of Alzheimer’s disease. It is not known if the ablation of Cav1 in these mice impacts the brain at the fetal stage that then influences brain function later in life. RNA-seq was performed to profile gene expression of fetal brain (gestation day 15) and aging brain (week 70) of Cav1 knockout mice. The data was comapred with genes expression data of fetal brain (gestation day 15) and aging brain (week 70) of wildtype mice from our earlier study.

2023-09-20 | GSE215139 | GEO

A molecular complex of Cav1.2/CaMKK2/CaMK1a in caveolae is responsible for vascular remodeling through excitation-transcription coupling in vascular smooth muscle.

Project description:Elevation of intracellular Ca2+ ([Ca2+]i) activates Ca2+/calmodulin-dependent kinases (CaMK) and promotes gene transcription. This essential signaling pathway is referred to as excitation-transcription (E-T) coupling. Although vascular myocytes can exhibit E-T coupling, the molecular mechanisms and physiological/pathological roles are unknown. Multiscale analysis spanning from single molecules to whole organisms has revealed essential steps in mouse vascular smooth muscle E-T coupling: (1) Upon depolarizing stimulus Ca2+ influx through voltage-dependent Ca2+ channel Cav1.2 activates CaMKK2, which results in phosphorylation of CaMK1a and CREB in the nucleus. (2) Within caveolae the formation of molecular complex of Cav1.2/CaMKK2/CaMK1a is promoted in the vascular myocytes. (3) Ca2+ influx through Cav1.2 localized to caveolae directly activates CaMKK2. (4) CaMK1a is phosphorylated by CaMKK2 at caveolae and translocated to the nucleus upon membrane depolarization. In addition, RNAseq analysis revealed that sustained depolarization of mesenteric artery preparation selectively induced genes related to chemotaxis, leukocyte adhesion and inflammation, and these changes were reversed by inhibitors of Cav1.2, CaMKK2 and CaMK or disruption of caveolae. In the context of pathophysiology, when mesenteric artery was loaded by high pressure in vivo, we noted CREB phosphorylation in myocytes, macrophage accumulation at adventitia, and increased thickness and cross-sectional area of tunica media. These changes were reduced in caveolin1-KO mice or in mice treated with a CaMKK2 inhibitor STO609. In summary, E-T coupling depend on Cav1.2/CaMKK2/CaMK1a localized to caveolae, and this molecular complex converts [Ca2+]i changes to gene transcription, leading to macrophage accumulation and media remodeling for adaptation to increased circumferential stretch.

2022-03-16 | GSE183588 | GEO

The ambiguous Caveolin-3 G55S sequence variant: Muscle biopsy findings and cell biological analysis

Project description:Caveolins are structural and functional proteins in plasma membrane invaginations called caveolae. Mutations in Caveolin-3 cause myopathies of variable severity. The pathogenicity of the Caveolin-3 variant G55S is still unclear. Here, we report on three patients suffering from mild to moderate myopathy. In all three patients, but also in two seemingly unaffected family members of patient one the G55S variant was found. Histology revealed moderate chronic myopathic changes and reduced sarcolemmal Caveolin-3 immunoreactivity in all three cases. Immunoblots for Caveolin-3 were abnormal in all cases. By electron microscopy, enlarged caveolae were detected in case one and three and vacuolar myopathy in case two. EM studies of RCMH myoblasts transfected with G55S Caveolin-3 revealed autophagic vacuoles. The alterations in Golgi morphology were in line with pathological Caveolin-3 deposits in this organelle detected by immunofluorescence and indicative for activation of autophagy. Phospho-blotting demonstrated that G55S affects EGFR signaling. Proteomic profiling of transfected RCMH myoblasts demonstrated alterations in levels of physiologically relevant proteins which are indicative for antagonization of G55S Caveolin-3 expression. Some proteomic alterations were enhanced by osmotic/mechanical stress. In conclusion, our results suggest that the G55S Caveolin-3 sequence variant can be compensated by cellular defense mechanisms and that additional stress may lead to vulnerability of G55S Caveolin-3 expressing muscle cells.

2018-07-05 | PXD003719 | Pride

caveolin-1 induced gene expression change in retinae

Project description:Caveolin-1 (Cav1) is the main structure protein of caveolae. Its main functional domain is the scaffolding domain that is the bind site of many interactors. A fused peptide called cavtratin is used to test Cav1 function which includes the scaffolding domain and a short internalizing peptide AP. Cav1 has been reported to be associated with glaucoma in the GWAS study. To explore its role in the retina, we explored the gene expression change after Cav1-shRNA or cavtratin was injected into the mouse eye vitreous.

2018-03-01 | GSE95657 | GEO

Multiomics Profiling Reveals Mitochondrial Metabolic Remodeling During Foam Cell Formation

Project description:Macrophages participate in plaque formation and development through the process of foam cell formation, and mitochondria play a crucial role in macrophage phenotype transformation. However, the mitochondrial metabolic characteristics of macrophages during foam cell formation have not been systematically studied. In this work, we investigated the mechanism of mitochondrial metabolic reprogramming during macrophage foam cell formation using proteomics, metabolomics and lipidomics. Multi-omics integrative analysis highlighted key metabolic pathway changes, including the tricarboxylic acid cycle fragmentation, and the recombination of mitochondria protein complexes and mitochondria membrane lipids.

2024-11-26 | PXD058260 |

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