Downregulation of Engulfment and cell motility 1 (Elmo1) induces quiescence and resistance to poly(I:C)-induced apoptosis in endothelial cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1272352 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33838407_1.fastq.gz | Fastqsanger.gz | |||
| SRR33838407_2.fastq.gz | Fastqsanger.gz | |||
| SRR33838408_1.fastq.gz | Fastqsanger.gz | |||
| SRR33838408_2.fastq.gz | Fastqsanger.gz | |||
| SRR33838409_1.fastq.gz | Fastqsanger.gz |
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Project description:Engulfment and Cell Motility 1 (ELMO1) facilitates activation of Ras-related C3 botulinum toxin substrate 1 (RAC1) through interaction with Dedicator of Cytokinesis (DOCK), a family of guanine nucleotide exchange factors (GEF). ELMO1 plays an important role in acute and chronic inflammation by enhancing immune cell migration, phagocytosis of pathogens and dead cells, and production of reactive oxygen species. Endothelial cells, an integral component of inflammatory responses, also express high levels of ELMO1, although the role of ELMO1 in inflammatory endothelial cells is unclear. We demonstrate that knockdown of ELMO1 in EA.hy926 human umbilical vein endothelial cells (HUVECs) leads to cell quiescence, while protects the cells from Toll-like receptor 3 (TLR3)-induced apoptosis and restores inflammatory responses.
2025-06-09 | GSE299038 | GEO
Project description:Rheumatoid arthritis is an inflammatory disease of the synovial joints that affects ~1% of the human population, with severe distress due to progressive joint inflammation and deformation. When addressing the links between specific components of the apoptotic cell clearance machinery and human disease, we noted a correlation between single nucleotide polymorphisms (SNPs) in ELMO1, DOCK2, and RAC1 genes and rheumatoid arthritis. ELMO1 is a cytoplasmic adapter protein that associates with DOCK2 and RAC1 to promote cytoskeletal reorganization needed for apoptotic cell uptake by phagocytes. We initially hypothesized that, since ELMO1 is linked to apoptotic cell clearance, loss of ELMO1 would lead to increased inflammation in arthritis. Contrary to the accumulation of apoptotic cells and greater disease severity that we predicted, we observed significantly reduced joint inflammation in two models of arthritis in mice lacking ELMO1. Using genetic and cell biological approaches in vivo and ex vivo, we determined that ELMO1 deficiency significantly reduces neutrophil recruitment to inflamed joints, but does not result in general inhibition of inflammatory responses. Through proteomic analyses, we find that ELMO1 protein associates with cellular receptors that contribute to neutrophil function in arthritis, and regulates C5a and LTB4 receptor-mediated activation and early neutrophil recruitment to the joints. Neutrophil-specific transcriptomics show that ELMO1 modulates neutrophil-specific gene expression that includes genes with known linkages to human arthritis. Finally, neutrophils from the peripheral blood of human donors that carry the SNP in ELMO1 associated with arthritis display increased migratory capacity, whereas ELMO1 knockdown reduces human neutrophil migration to LTB4. These data identify key ‘non-canonical’ roles for engulfment machinery components in arthritis, and ELMO1 as an important regulator of specific neutrophil receptors and signaling linked to arthritis.
2019-03-19 | GSE122412 | GEO
Project description:Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and a key contributor to the progression toward chronic kidney disease (CKD), with oxidative stress playing a central role in this transition. Engulfment and Cell Motility 1 (ELMO1) regulates cytoskeletal remodeling and reactive oxygen species (ROS) production through RAC1 activation, yet its involvement in redox imbalance and kidney injury remains unclear. To investigate this, a unilateral renal IRI model was established in wild-type (WT) and ELMO1-overexpressing (Elmo1 H/H) mice. Renal function was evaluated using plasma cystatin C, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR), while structural and ultrastructural kidney changes were assessed by Masson’s trichrome staining and electron microscopy. Redox-related gene expression was analyzed via RT-qPCR, and global transcriptional alterations were examined using RNA sequencing.
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Project description:Engulfment gene ELMO1 in neutrophils as a promoter of inflammatory arthritis
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Project description:Elmo1 is one member of the Elmo protein family. In our study we addressed the question if the functions of Elmo1, Elmo2 and Elmo3 are consistent or if they differ. With the CRISPR/Cas9 system we generated single knockout mutants of elmo1, elmo2 and elmo3 in the zebrafish. To assess the impact of the loss of one of the proteins on the transcriptome of a developing organism, we did RNA sequencing and transcriptome analysis with elmo1+/+ and elmo1-/-, elmo2+/+ and elmo2-/- and elmo3+/+ and elmo3-/- zebrafish larvae at 120 hours post fertilization. Here we provide the sequencing data of elmo1+/+ and elmo1-/-.
2022-07-25 | GSE197824 | GEO
Project description:Osteoporosis and bone fractures affect millions of men and women worldwide and are often due to increased bone resorption (bone loss) mediated by osteoclasts. Here, we identify a novel role for the cytoplasmic protein ELMO1 as an important ‘signaling node’ controlling the bone resorption function of osteoclasts. Initially, we noted association of ELMO1 SNPs with bone abnormalities and altered bone density in humans. Experimentally, ELMO1 emerged as a promoter of bone loss wherein deletion of ELMO1 reversed osteoporosis / bone erosions in four in vivo mouse models: osteoprotegerin deficiency, ovariectomy, and two types of inflammatory arthritis. However, ELMO1 did not promote bone loss under homeostatic conditions. Mechanistic studies pointed to a larger ELMO1 signaling network that regulates osteoclast activity at several levels. First, transcriptomics coupled with CRISPR/Cas9 genetic deletion approaches identified new regulators of osteoclast function associated with Elmo1, including cathepsin G and myeloperoxidase. Second, defining the ‘ELMO1 interactome’ in osteoclasts via proteomics revealed membrane proteins and v-ATPases required for bone degradation. Third, ELMO1 affects the formation of the actin ring /sealing zone on bone-like surfaces and the distribution of osteoclast-specific proteases. Finally, a 3D structure-based inhibitory peptide targeting a highly conserved region of ELMO1 reduced bone resorption in wild type osteoclasts. Collectively, these data identify ELMO1 as a signaling hub that regulates osteoclast function and bone loss, with relevance to diseases such as osteoporosis and arthritis.
2021-06-05 | GSE164826 | GEO
Project description:Osteoporosis and bone fractures affect millions of men and women worldwide and are often due to increased bone resorption (bone loss) mediated by osteoclasts. Here, we identify a novel role for the cytoplasmic protein ELMO1 as an important ‘signaling node’ controlling the bone resorption function of osteoclasts. Initially, we noted association of ELMO1 SNPs with bone abnormalities and altered bone density in humans. Experimentally, ELMO1 emerged as a promoter of bone loss wherein deletion of ELMO1 reversed osteoporosis / bone erosions in four in vivo mouse models: osteoprotegerin deficiency, ovariectomy, and two types of inflammatory arthritis. However, ELMO1 did not promote bone loss under homeostatic conditions. Mechanistic studies pointed to a larger ELMO1 signaling network that regulates osteoclast activity at several levels. First, transcriptomics coupled with CRISPR/Cas9 genetic deletion approaches identified new regulators of osteoclast function associated with Elmo1. Second, defining the ‘ELMO1 interactome’ in osteoclasts via proteomics revealed proteins linked to bone degradation. Third, ELMO1 affects the formation of the actin ring /sealing zone on bone-like surfaces and the distribution of osteoclast-specific proteases. Finally, a 3D structure-based inhibitory peptide targeting a highly conserved region of ELMO1 reduced bone resorption in wild type osteoclasts. Collectively, these data identify ELMO1 as a signaling hub that regulates osteoclast function and bone loss, with relevance to diseases such as osteoporosis and arthritis.
2021-06-07 | PXD023578 | Pride
Project description:Sickle cell disease (SCD) and apolipoprotein L1 (APOL1) G1/G2 variants increase chronic kidney disease (CKD) risk in African Americans by poorly understood mechanisms. We applied bioinformatics to identify new candidate genes associated with SCD-related CKD. An interaction network demonstrated APOA1 connecting haemoglobin subunit β (HBB) and APOL1 with 36 other candidate genes. Gene expression revealed upregulation of engulfment and cell motility 1 (ELMO1) and downregulation of APOA1 in the kidney cortex of SCD versus non-SCD mice. Analysis of candidate genes identified ELMO1 rs10951509 to be associated with albuminuria and APOA1 rs11216132 with haemoglobinuria in patients with SCD. A bioinformatic approach highlights ELMO1 and APOA1 as potentially associated with SCD nephropathy.
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Project description:Motility in Listeria monocytogenes is negatively regulated within the mammalian host in response to temperature through a complex interplay between positively acting and negatively acting regulators. Motility genes are expressed under saprophytic conditions where the temperature is 30ºC or less. Motility is costly on cellular resources due to the large molecular structures that need to be synthesized, and the proton motive force required to produce flagellar rotation. Under stressful environmental conditions there is a trade off between motility and energy conservation and bacteria typically repress motility when adverse conditions are encountered. Here we investigated the impact of the SigB-mediated general stress response on the regulation of motility in L. monocytogenes and sought to elucidate the regulatory steps involved. We show that an rsbX mutation that compromises the ability to inactivate the stressosome, the sensory hub at the top of the SigB activation pathway, results in motility repression. Escaping from this repressed state occurred through the acquisition of mutations that decreased SigB activity. Flagellar expression was abolished in these mutants and a transcriptomic analysis revealed that the entire flagellar operon is strongly repressed. The motility anti-repressor gene gmaR was also downregulated in an ΔrsbX background. These effects can be reversed by providing functional copies of rsbX or gmaR in trans. Deletion of an internal SigB dependent promoter that produces an antisense RNA for the large motility operon (including gmaR) restores the ability to produce flagellin in the ΔrsbX background. A similar phenotype is observed by deleting MogR, which acts as a negative regulator of flagella motility. Stressosome mutations that negatively affect SigB activity result in derepressed motility whereas those that increase SigB activity result in a decreased motility phenotype similar to the ΔrsbX strain. Overall, the data indicate that stress sensing via the stressosome negatively impacts motility in L. monocytogenes and shows that the general stress response can take priority over motility when L. monocytogenes encounters harsh environmental conditions.
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Project description:Apoptotic cell death is essential for development and tissue homeostasis. Failure to clear apoptotic cells can ultimately cause inflammation and autoimmunity. Apoptosis has primarily been studied by staining of fixed tissue sections, and a clear understanding of the behavior of apoptotic cells in living tissue has been elusive. Here, we use a newly developed technique to track apoptotic cells in real time as they emerge and are cleared from the zebrafish brain. We find that apoptotic cells are remarkably motile, frequently migrating several cell diameters to the periphery of living tissues. F-actin remodeling occurs in surrounding cells, but also within the apoptotic cells themselves, suggesting a cell-autonomous component of motility. During the first 2 days of development, engulfment is rare, and most apoptotic cells lyse at the brain periphery. By 3 days postfertilization, most cell corpses are rapidly engulfed by macrophages. This engulfment requires the guanine nucleotide exchange factor elmo1. In elmo1-deficient macrophages, engulfment is rare and may occur through macropinocytosis rather than directed engulfment. These findings suggest that clearance of apoptotic cells in living vertebrates is accomplished by the combined actions of apoptotic cell migration and elmo1-dependent macrophage engulfment.
| S-EPMC3597770 | biostudies-literature