ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation
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...
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MDPI AG
2021-10-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/11/2962 |
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| author | Anna Santarsiero Paolo Convertini Simona Todisco Ciro L. Pierri Anna De Grassi Niamh C. Williams Dominga Iacobazzi Giulio De Stefano Luke A. J. O’Neill Vittoria Infantino |
| author_facet | Anna Santarsiero Paolo Convertini Simona Todisco Ciro L. Pierri Anna De Grassi Niamh C. Williams Dominga Iacobazzi Giulio De Stefano Luke A. J. O’Neill Vittoria Infantino |
| author_sort | Anna Santarsiero |
| collection | DOAJ |
| description | 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 <i>SLC25A1</i>—which encodes the mitochondrial citrate carrier—and <i>ACLY</i>, thus promoting the existence of a proinflammatory loop involving <i>SLC25A1</i> and <i>ACLY</i> genes. |
| first_indexed | 2024-03-10T05:37:15Z |
| format | Article |
| id | doaj.art-4c0373f557ba404185f721458bb1f4e7 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T05:37:15Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-4c0373f557ba404185f721458bb1f4e72023-11-22T22:49:19ZengMDPI AGCells2073-44092021-10-011011296210.3390/cells10112962ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB AcetylationAnna Santarsiero0Paolo Convertini1Simona Todisco2Ciro L. Pierri3Anna De Grassi4Niamh C. Williams5Dominga Iacobazzi6Giulio De Stefano7Luke A. J. O’Neill8Vittoria Infantino9Department of Science, University of Basilicata, 85100 Potenza, ItalyDepartment of Science, University of Basilicata, 85100 Potenza, ItalyDepartment of Science, University of Basilicata, 85100 Potenza, ItalyDepartment of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125 Bari, ItalyDepartment of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125 Bari, ItalyTrinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, D02 R590 Dublin, IrelandBristol Heart Institute, Bristol Medical School, University of Bristol, Bristol BS2 8HW, UKDepartment of Infectious Diseases, San Carlo Hospital, Via Potito Petrone, 85100 Potenza, ItalyTrinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, D02 R590 Dublin, IrelandDepartment of Science, University of Basilicata, 85100 Potenza, ItalyMacrophage 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 <i>SLC25A1</i>—which encodes the mitochondrial citrate carrier—and <i>ACLY</i>, thus promoting the existence of a proinflammatory loop involving <i>SLC25A1</i> and <i>ACLY</i> genes.https://www.mdpi.com/2073-4409/10/11/2962ACLYinflammationmacrophagesnuclear translocationNF-κBp65 acetylation |
| spellingShingle | Anna Santarsiero Paolo Convertini Simona Todisco Ciro L. Pierri Anna De Grassi Niamh C. Williams Dominga Iacobazzi Giulio De Stefano Luke A. J. O’Neill Vittoria Infantino ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation Cells ACLY inflammation macrophages nuclear translocation NF-κB p65 acetylation |
| title | ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation |
| title_full | ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation |
| title_fullStr | ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation |
| title_full_unstemmed | ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation |
| title_short | ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation |
| title_sort | acly nuclear translocation in human macrophages drives proinflammatory gene expression by nf κb acetylation |
| topic | ACLY inflammation macrophages nuclear translocation NF-κB p65 acetylation |
| url | https://www.mdpi.com/2073-4409/10/11/2962 |
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