ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation.
Anna SantarsieroPaolo ConvertiniSimona TodiscoCiro Leonardo PierriAnna De GrassiNiamh C WilliamsDominga IacobazziGiulio De StefanoLuke A J O'NeillVittoria InfantinoPublished in: Cells (2021)
Macrophage stimulation by pathogen-associated molecular patterns (PAMPs) like lipopolysaccharide (LPS) or lipoteichoic acid (LTA) drives a proinflammatory phenotype and induces a metabolic reprogramming to sustain the cell's function. Nevertheless, the relationship between metabolic shifts and gene expression remains poorly explored. In this context, the metabolic enzyme ATP citrate lyase (ACLY), the producer of citrate-derived acetyl-coenzyme A (CoA), plays a critical role in supporting a proinflammatory response. Through immunocytochemistry and cytosol-nucleus fractionation, we found a short-term ACLY nuclear translocation. Protein immunoprecipitation unveiled the role of nuclear ACLY in NF-κB acetylation and in turn its full activation in human PBMC-derived macrophages. Notably, sepsis in the early hyperinflammatory phase triggers ACLY-mediated NF-κB acetylation. The ACLY/NF-κB axis increases the expression levels of proinflammatory genes, including SLC25A1-which encodes the mitochondrial citrate carrier-and ACLY, thus promoting the existence of a proinflammatory loop involving SLC25A1 and ACLY genes.
Keyphrases
- gene expression
- lps induced
- signaling pathway
- oxidative stress
- endothelial cells
- inflammatory response
- pi k akt
- nuclear factor
- dna methylation
- genome wide
- acute kidney injury
- toll like receptor
- histone deacetylase
- binding protein
- immune response
- cell proliferation
- pluripotent stem cells
- protein protein
- long non coding rna
- fatty acid
- cell therapy
- bioinformatics analysis
- single molecule