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Elevated levels of S100A8 and S100A9 exacerbate muscle mitochondrial fragmentation in sepsis-induced muscle atrophy

ABSTRACT: Elevated levels of S100A8 and S100A9 exacerbate muscle mitochondrial fragmentation in sepsis-induced muscle atrophy

PROVIDER: PRJNA1202508 | ENA |

REPOSITORIES: ENA

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Elevated levels of S100A8 and S100A9 exacerbate muscle mitochondrial fragmentation in sepsis-induced muscle atrophy

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S100A8/S100A9 cytokine functions as transcriptional coactivator during breast cellular transformation

Project description:In an inducible model of human breast cellular transformation, we map genome-wide chromatin binding of S100A8, S100A9 and Pol II. We show that the calcium-dependent cytokines S100A8 and S100A9 are recruited to numerous promoters and enhancers. This recruitment is associated with multiple DNA sequence motifs recognized by DNA-binding transcription factors that are linked to transcriptional activation and are important for transformation. Nuclear-specific expression of S100A8/A9 promotes oncogenic transcription and leads to enhanced breast transformation phenotype. These results suggest that, in addition to its classical cytokine function, S100A8/A9 can act as a transcriptional co-activator.

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Local restriction of sterile inflammation by auto-inhibitory regulation of S100A8/S100A9-alarmin activity

Project description:Autoimmune diseases, like psoriasis or arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals like Danger-Associated Molecular Pattern molecules (DAMPs) are indispensable for manifestation of local inflammation. S100A8/100A9-complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP-activities are barely understood. We now unravel for the first time a novel mechanism of auto-inhibition in mice and man restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry and targeted mutations we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9-heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9-activities are locally restricted by calcium-induced (S100A8/S100A9)2-tetramer formation now hiding the TLR4/MD2-binding site within the tetramer interphase thus preventing undesirable systemic effects. Loss of this auto-inhibitory mechanism in vivo results in TNFa-driven fatal inflammation as shown by lack of tetramer formation crossing S100A9-/- mice with two independent TNFa-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking of the TLR4-binding site of active S100-dimers represents an innovative approach for local suppression of inflammatory diseases avoiding systemic side effects.

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S100A8 treatment on gene expression of human umbilical vascular endothelial cells.

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A proteome-wide screen identifies the calcium binding proteins, S100A8/S100A9, as clinically relevant therapeutic targets in aortic dissection: a translational study [scRNA-seq]

Project description:S100A8 and S100A9 (aliases MRP8 and MRP14) are highly expressed in neutrophils and monocytes and are classified as damage-associated molecular pattern (DAMP) molecules or alarm molecules. However, the role of S100A8/A9 in aortic dissection has not been reported. In the present study, by employing an unbiased proteomics approach and RNA sequencing analysis , we found that the protein expression of calcium binding proteins S100A8/A9 were upregulated in the aorta and serum of TAAAD patients and also in a mouse model.

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S100A8 treatment on gene expression of human umbilical vascular endothelial cells.

2011-11-20 | GSE33768 | GEO