title: Identification of the NF-κB inhibitor A20 as a key regulator for human adipogenesis.
abstract: The zinc-finger protein A20 is a key player in the negative feedback regulation of the nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) pathway in response to multiple stimuli. Tumor necrosis factor alpha (TNFα), a cytokine with pleiotropic effects on cellular proliferation and differentiation, dramatically increases A20 expression in all tissues. As TNFα inhibits adipocyte differentiation, we have determined the contribution of A20 to the adipogenic capacity of human mesenchymal stromal cells (MSCs). Here we show that A20 is constitutively expressed in MSCs, which previously has been observed only in cells that are either tumor or immune cells (T/B lymphocytes). TNFα stimulation induced a rapid degradation of A20 protein mediated exclusively by the proteasome in MSCs and not by caspases. This degradation is concomitant to the induction of its own mRNA, which suggests that a tight regulation of NF-κB signaling in MSCs is fundamental. On one hand, we demonstrate that the knockdown of A20-mediated transcript dramatically decreases the adipogenic capacity of MSCs, which correlates with the phenotype observed in the presence of TNFα. On the other hand, A20 overexpression blocks NF-κB activation and drives to increased adipogenesis, even in the presence of TNFα treatment. In conclusion, our data demonstrate that the presence of A20 allows MSCs to differentiate into adipocytes by maintaining NF-κB signaling at a basal state.
authors.affiliation: Mesenchymal and Hematopoietic Stem Cell Department, Fundación Inbiomed, Foundation for Stem Cell Research, Paseo Mikeletegi, 81, 20009 San Sebastián, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Dorronsoro
authors.affiliation: Ubiquitylation and Cancer Molecular Biology Laboratory, Fundación Inbiomed, Foundation for Stem Cell Research, Paseo Mikeletegi, 81, 20009 San Sebastián, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Lang
authors.affiliation: Mesenchymal and Hematopoietic Stem Cell Department, Fundación Inbiomed, Foundation for Stem Cell Research, Paseo Mikeletegi, 81, 20009 San Sebastián, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Jakobsson
authors.affiliation: Mesenchymal and Hematopoietic Stem Cell Department, Fundación Inbiomed, Foundation for Stem Cell Research, Paseo Mikeletegi, 81, 20009 San Sebastián, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Ferrin
authors.affiliation: Mesenchymal and Hematopoietic Stem Cell Department, Fundación Inbiomed, Foundation for Stem Cell Research, Paseo Mikeletegi, 81, 20009 San Sebastián, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Salcedo
authors.affiliation: Mesenchymal and Hematopoietic Stem Cell Department, Fundación Inbiomed, Foundation for Stem Cell Research, Paseo Mikeletegi, 81, 20009 San Sebastián, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Fernández-Rueda
authors.affiliation: Mesenchymal and Hematopoietic Stem Cell Department, Fundación Inbiomed, Foundation for Stem Cell Research, Paseo Mikeletegi, 81, 20009 San Sebastián, Spain.
authors.forename: K
authors.initials: K
authors.lastname: Fechter
authors.affiliation: Ubiquitylation and Cancer Molecular Biology Laboratory, Fundación Inbiomed, Foundation for Stem Cell Research, Paseo Mikeletegi, 81, 20009 San Sebastián, Spain.
authors.forename: M S
authors.initials: MS
authors.lastname: Rodriguez
authors.affiliation: Mesenchymal and Hematopoietic Stem Cell Department, Fundación Inbiomed, Foundation for Stem Cell Research, Paseo Mikeletegi, 81, 20009 San Sebastián, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Trigueros
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3