Abstract
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.
Highlights
Post-translational modifications (PTMs) of proteins regulate a wide range of their biological functions such as gene expression and protein localization and activity
Six hours after LPS treatment, a second ATP citrate lyase (ACLY) increase was present, followed by a rapid decrease (Figure 1b). These results revealed a rise in the ACLY protein content first (1 h after LPS addition; Figure 1b) before its transcriptional activation (i.e., earlier than the first mRNA peak observed 3 h after LPS stimulation (Figure 1a))
Following the results described above, we wondered if ACLY-mediated p65 acetylation may affect nuclear factorκB (NF-κB) binding to its target gene promoters
Summary
Post-translational modifications (PTMs) of proteins regulate a wide range of their biological functions such as gene expression and protein localization and activity. Acetylation of lysine residues is among the best-studied PTMs, especially relating to histone proteins, which need acetyl-CoA as an acetyl group donor. Several studies in yeast as well as in mammalian cells have highlighted the link between intracellular acetyl-CoA levels and protein acetylation [1]. Protein acetylation may represent a fast way to control protein activities through metabolic changes such as acetyl-CoA fluctuations. Acetyl-CoA is mainly supplied by ATP citrate lyase (ACLY) activity [2], when the tricarboxylic acid (TCA) cycle of intermediate citrate—generated either from glucose or glutamine—moves from the mitochondria to the cytosol through the mitochondrial citrate carrier (CIC) encoded by the SLC25A1 gene. Mitochondrial citrate export leads to the production of acetyl-CoA and oxaloacetate via ACLY
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
