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

Autor: Riedlinger T; Institute of Biochemistry, Medical Faculty, Friedrichstrasse 24, Justus-Liebig-University, D-35392 Giessen, Germany., Dommerholt MB; Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands., Wijshake T; Section of Molecular Genetics, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands; Departments of Pediatrics and Adolescent Medicine, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN, USA., Kruit JK; Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands., Huijkman N; Section of Molecular Genetics, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands., Dekker D; Section of Molecular Genetics, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands., Koster M; Section of Molecular Genetics, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands., Kloosterhuis N; Section of Molecular Genetics, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands., Koonen DPY; Section of Molecular Genetics, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands., de Bruin A; Section of Molecular Genetics, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands; Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands., Baker D; Departments of Pediatrics and Adolescent Medicine, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN, USA., Hofker MH; Section of Molecular Genetics, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands., van Deursen J; Departments of Pediatrics and Adolescent Medicine, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN, USA., Jonker JW; Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands., Schmitz ML; Institute of Biochemistry, Medical Faculty, Friedrichstrasse 24, Justus-Liebig-University, D-35392 Giessen, Germany., van de Sluis B; Section of Molecular Genetics, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands. Electronic address: a.j.a.van.de.sluis@umcg.nl.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular cell research [Biochim Biophys Acta Mol Cell Res] 2017 Oct; Vol. 1864 (10), pp. 1785-1798. Date of Electronic Publication: 2017 Jul 16.
DOI: 10.1016/j.bbamcr.2017.07.005
Abstrakt: 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.
(Copyright © 2017 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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