Cardiomyocyte βII Spectrin Plays a Critical Role in Maintaining Cardiac Function via Regulating Mitochondrial Respiratory Function
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE228508 | GEO | 2026/03/02
REPOSITORIES: GEO
Similar Datasets
Project description:Cardiomyocyte βII Spectrin Plays a Critical Role in Maintaining Cardiac Function via Regulating Mitochondrial Respiratory Function
| PRJNA950076 | ENA
Project description:Gene expression profiling was carried out in wild and β2SP-/- (Sptbn1 -/-) mouse embryonic fibroblast (MEF) cells. Beta-2-spectrin (β2SP) is a dynamic intracellular non-pleckstrin homology (PH)-domain protein that belongs to a family of polypeptides that have been implicated in conferring cell polarity. Spectrins have been linked to multiple signaling pathways, including cell cycle regulation, DNA repair and TGFβ signaling. In this study, we report a major role of the TGFβ/Smad3 adaptor β2-Spectrin in conserving genomic integrity from alcohol-induced DNA damage and describe a novel pathway that protects genomes from genotoxic stresses.
2016-02-17 | GSE65987 | GEO
Project description:Gene expression profiling was carried out in wild and β2SP-/- (Sptbn1 -/-) mouse embryonic fibroblast (MEF) cells. Beta-2-spectrin (β2SP) is a dynamic intracellular non-pleckstrin homology (PH)-domain protein that belongs to a family of polypeptides that have been implicated in conferring cell polarity. Spectrins have been linked to multiple signaling pathways, including cell cycle regulation, DNA repair and TGFβ signaling. In this study, we report a major role of the TGFβ/Smad3 adaptor β2-Spectrin in conserving genomic integrity from alcohol-induced DNA damage and describe a novel pathway that protects genomes from genotoxic stresses. Whole-transcriptome RNA sequencing of wild-type and β2SP knockout (β2SP-/-) mouse embryonic fibroblasts was carried out on an Illumina HiSeq 2000 sequencer. The raw data quality was assessed using a FastQC software. Adaptor presence was tested using Trimmomatic. The readings were then aligned to the NCBI mouse reference genome build 37.2 using the splice-aware aligner Tophat2 v2.0.10. Transcript quantification, normalization and assembly were carried out with Cufflinks. A gene model gtf file corresponding to the NCBI mouse reference genome build 37.2 was used in the quantification. Cuffdiff2, part of the Cufflinks suite of tools, was used to identify significant differences in gene expression profiles between the wild-type and β2SP-/- MEF cells.
2016-02-17 | E-GEOD-65987 | biostudies-arrayexpress
Project description:Axon degeneration sculpts precise patterns of connectivity in the developing nervous system and is an early pathological hallmark of several adult-onset neurodegenerative disorders. Substantial progress has been made in identifying effector mechanisms that drive axon fragmentation, but far less is known about the upstream signaling pathways that initiate this process. Here we describe a role for the newly discovered axonal Membrane-associated Periodic Skeleton (MPS) –a quasi-1D periodic ultrastructure composed of actin, spectrin and associated molecules– during sensory axon degeneration. We find that trophic deprivation (TD) of sensory axons causes a rapid breakdown in the periodicity of the MPS in distal axons. These structural changes occur prior to and independently of caspase-driven axon fragmentation. We further show that acute actin destabilization to break down the MPS can initiate TD-related retrograde signaling. Actin stabilization prevents MPS breakdown during TD and blocks this signal. Moreover, deletion of βII-spectrin (Sptbn1), an obligate component of the MPS, suppresses this retrograde signaling and protects axons against degeneration. Together our data suggest that ultrastructural plasticity of the MPS underlies the earliest steps of axon degeneration.
2019-03-14 | PXD009854 | Pride
Project description:The susceptibility of macrophages to HIV-1 infection is modulated during monocyte differentiation. IL-27 is an anti-HIV cytokine that also modulates monocyte activation. Here, we present new evidence that IL-27 promotes monocyte differentiation into macrophages that are non-permissive for HIV-1 infection. While IL-27 treatment does not affect expression of macrophage differentiation markers or macrophage biological functions, it confers HIV resistance by down-regulating spectrin beta non-erythrocyte 1 (SPTBN1), a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 through a TAK-1-mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27 treated macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect macrophages from HIV-1 infection by down-regulating SPTBN1, thus indicating that SPTBN1 is an important host target to reduce HIV-1 replication in one major element of the viral reservoir. 2 samples with different treatments were analyzed. Genes with absolute fold change >= 5 were selected.
2013-01-18 | E-GEOD-43595 | biostudies-arrayexpress
Project description:The susceptibility of macrophages to HIV-1 infection is modulated during monocyte differentiation. IL-27 is an anti-HIV cytokine that also modulates monocyte activation. Here, we present new evidence that IL-27 promotes monocyte differentiation into macrophages that are non-permissive for HIV-1 infection. While IL-27 treatment does not affect expression of macrophage differentiation markers or macrophage biological functions, it confers HIV resistance by down-regulating spectrin beta non-erythrocyte 1 (SPTBN1), a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 through a TAK-1-mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27 treated macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect macrophages from HIV-1 infection by down-regulating SPTBN1, thus indicating that SPTBN1 is an important host target to reduce HIV-1 replication in one major element of the viral reservoir.
2013-01-18 | GSE43595 | GEO
Project description:Background: Cardiac hypertrophy, defined as a stress-induced increase in heart mass/size, is a major risk factor for adverse cardiovascular events including heart failure and arrhythmia. Within this general definition, the orientation of cell and organ growth varies considerably depending on stress type and duration with important implications for cardiac function, yet, little is known regarding the mechanisms that regulate hypertrophic orientation. Here, we evaluated the role of the cytoskeletal protein βIV-spectrin and associated pro-hypertrophic signal transducer and activator of transcription (STAT3) to direct the orientation of hypertrophic growth. Methods: Transgenic mouse models with altered STAT3 signaling through modified interaction with its scaffolding partner βIV-spectrin, or phospho-regulation of STAT3 directly, were evaluated at baseline, and following transaortic constriction (TAC), or aortocaval fistula (ACF). Unbiased screening of gene expression from these structurally divergent states were evaluated for pathways responsible for directing myocyte length/width. These pathways were tested in vitro using primary mouse myocytes and in vivo to tune growth patterns for therapeutic intervention. Results: Loss of βIV-spectrin or direct STAT3 activation promoted a preferential increase in myocyte length over width, resulting in dilation of the left ventricular (LV) chamber (eccentric hypertrophy) and decreased systolic function. Conversely, preservation of βIV-spectrin favored an increase in myocyte width without LV dilation (concentric hypertrophy) and preserved systolic function in response to TAC or ACF. Differential expression of genes associated with microtubules, including the trafficking kinesin motor, KIF20A, were identified in concentric vs. eccentric hypertrophic states. In vitro assays revealed a relationship between βIV-spectrin/STAT3 signaling, KIF20A expression, microtubule density, and spatial distribution of mRNA for the sarcomeric gene actc1. Finally, intervention with pharmacologic STAT3 inhibition following chronic 6-week TAC successfully recovered concentric growth with improved systolic function. Conclusions: These data identify a novel and pivotal role for βIV-spectrin/STAT3 to direct myocyte geometry in response to chronic stress. These studies further illustrate the unique separation of hypertrophic growth and orientation as distinct pathways in cardiac remodeling.
2025-10-08 | GSE302522 | GEO
Project description:Fibrosis is a pronounced feature of heart disease and the result of dysregulated activation of resident cardiac fibroblasts (CFs). Recent work identified stress-induced degradation of the cytoskeletal protein βIV-spectrin as an important step in CF activation and cardiac fibrosis. Further, loss of βIV-spectrin was found to depend on Ca2+/calmodulin-dependent kinase II (CaMKII). Therefore, we sought to determine the mechanism for CaMKII-dependent regulation of βIV-spectrin and CF activity. Computational screening and mass spectrometry revealed a critical serine residue (S2250 in mouse, S2254 in human) in βIV-spectrin phosphorylated by CaMKII. Disruption of βIV-spectrin/CaMKII interaction or ablation of βIV-spectrin Ser2250 through alanine substitution (βIV-S2250A) prevented CaMKII-induced degradation, while a phospho-mimetic construct (βIV-S2254E) showed accelerated degradation in the absence of CaMKII. To assess the physiological significance of this phosphorylation event, we expressed exogenous βIV-S2254A and βIV-S2254E constructs in βIV-spectrin-deficient CFs, which have increased proliferation and fibrotic gene expression compared to wild-type (WT). βIV-S2254A but not βIV-S2254E normalized proliferation and gene expression. Pathophysiologic targeting of βIV-spectrin phosphorylation and subsequent degradation was identified in CFs activated with the profibrotic ligand angiotensin II (AngII), resulting in increased proliferation and STAT3 nuclear accumulation. While therapeutic delivery of exogenous WT βIV-spectrin partially reversed these trends, βIV-S2254A completely negated increased CF proliferation and STAT3 translocation. Moreover, we observed βIV-spectrin phosphorylation and associated loss in total protein within human heart failure (HF) tissue. Together, these data illustrates a considerable role for the βIV-spectrin/CaMKII interaction in activating profibrotic signaling.
2022-02-17 | PXD025776 | Pride
Project description:Colorectal cancer (CRC) incidence is rising globally and anticipated to become the leading cause of cancer death in younger individuals. Potential risk factors are diet induced obesity and altered microbiomes that lead to accumulation of toxic metabolite accumulation. However, how ammonia and other microbial metabolites impact key signaling pathways, such as TGF-β signaling, to promote CRC remains unclear. Our study investigates a critical link between gut microbiome alterations, ammonia, and their toxic effects on the TGF-β signaling pathway, to drive CRC progression. We found that in an obesity induced mouse model of cancer, altered microbial populations and ammonia promote Caspase-3-mediated cleavage of SMAD3 adaptor βII-spectrin (SPTBN1). Cleaved SPTBN1 fragments form adducts with ammonia to induce pro-inflammatory cytokine expression and alter TGF-β signaling driving CRC. Extending on Alphafold docking simulations, we identified that ammonia interacts with six polar residues at SPTBN1 (S553, Y556, S663, Y666, N986, and T1178) of cleaved SPTBN1 fragments to form hydrogen bonds that disrupt downstream SMAD3 signaling, altering TGF-β signaling to a protumorigenic phenotype. Blocking SPTBN1, through an SPTBN1 specific siRNA blocks ammonia toxicity and restore TGF-β signaling by reducing the abundance of SPTBN1 cleaved fragments. Importantly, SPTBN1 siRNA blocks ammonia toxicity and restore normal TGF-β signaling in CRC cells. Moreover, our research establishes crosstalk between TGF-β signaling and a microbial sensor, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is significantly overexpressed in CRC patients. We identified CEACAM1-SPTBN1 interactions at specific residues (E517 and Y520) within the immunoreceptor tyrosine-based inhibitory motif (ITIM) of CEACAM1 cytoplasmic domain, with both molecules playing pivotal roles in CRC progression. Our study identifies mechanistic insights into how microbial metabolites target TGF-β a major signaling pathways to promote CRC.
2024-11-16 | GSE281613 | GEO
Project description: Not available
| S-EPMC4260630 | biostudies-literature