NF-κB p65 serine 467 phosphorylation sensitizes mice to weight gain and TNFα-or diet-induced inflammation

• Published in: Biochimica et biophysica acta. Molecular cell research Vol. 1864; no. 10; pp. 1785 - 1798
• Main Authors: Riedlinger, Tabea, Dommerholt, Marleen B., Wijshake, Tobias, Kruit, Janine K., Huijkman, Nicolette, Dekker, Daphne, Koster, Mirjam, Kloosterhuis, Niels, Koonen, Debby P.Y., de Bruin, Alain, Baker, Darren, Hofker, Marten H., van Deursen, Jan, Jonker, Johan W., Schmitz, M. Lienhard, van de Sluis, Bart
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2017
• Subjects: Aging; Aging - genetics; Aging - metabolism; Aging - pathology; Amino Acid Substitution - genetics; Animals; Gene expression; Gene Expression Regulation; Gene Knock-In Techniques; Humans; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Insulin; Insulin - metabolism; Liver - metabolism; Liver - pathology; Metabolism; Mice; Obesity; Obesity - genetics; Obesity - metabolism; Obesity - pathology; Phosphorylation; Serine - metabolism; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Tumor Necrosis Factor-alpha - metabolism; Weight Gain - genetics; Aging; Obesity; Inflammation; Metabolism; Gene expression; Insulin
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2017.07.005

The NF-κB family of transcription factors is essential for an effective immune response, but also controls cell metabolism, proliferation and apoptosis. Its broad relevance and the high connectivity to diverse signaling pathways require a tight control of NF-κB activity. To investigate the control of NF-κB activity by phosphorylation of the NF-κB p65 subunit, we generated a knock-in mouse model in which serine 467 (the mouse homolog of human p65 serine 468) was replaced with a non-phosphorylatable alanine (S467A). This substitution caused reduced p65 protein synthesis and diminished TNFα-induced expression of a selected group of NF-κB-dependent genes. Intriguingly, high-fat fed S467A mice displayed increased locomotor activity and energy expenditure, which coincided with a reduced body weight gain. Although glucose metabolism or insulin sensitivity was not improved, diet-induced liver inflammation was diminished in S467A mice. Altogether, this study demonstrates that phosphorylation of p65 serine 467 augment NF-κB activity and exacerbates various deleterious effects of overnutrition in mice. •Phosphorylation of p65 S467 is required for accurate selective NF-κB-mediated gene expression.•p65 serine 467 phosphorylation improves de novo p65 protein synthesis.•Preventing phosphorylation of p65 S467 diminishes the inflammatory response.•Phosphorylation of p65 S467 protects mouse fibroblast cells to TNF-induced apoptosis.•p65 serine 467 phosphorylation sensitizes mice to weight gain.