title: Polyubiquitination of transforming growth factor β (TGFβ)-associated kinase 1 mediates nuclear factor-κB activation in response to different inflammatory stimuli.
abstract: The transcription factor nuclear factor κB (NF-κB) plays a central role in regulating inflammation in response to several external signals. The TGFβ-associated kinase 1 (TAK1) is an upstream regulator of NF-κB signaling. In TGFβ-stimulated cells, TAK1 undergoes Lys-63-linked polyubiquitination at Lys-34 by TNF receptor-associated factor 6 and is thereby activated. The aim of this study was to investigate whether TAK1 polyubiquitination at Lys-34 is also essential for NF-κB activation via TNF receptor, IL-1 receptor and toll-like receptor 4. We observed that TAK1 polyubiquitination occurred at Lys-34 and required the E3 ubiquitin ligase TNF receptor-associated factor 6 after stimulation of cells with IL-1β. Polyubiquitination of TAK1 also occurred at Lys-34 in cells stimulated by TNF-α and LPS, which activates TLR4, as well as in HepG2 and prostate cancer cells stimulated with TGFβ, which in all cases resulted in NF-κB activation. Expression of a K34R-mutant TAK1 led to a reduced NF-κB activation, IL-6 promoter activity, and proinflammatory cytokine secretion by TNF-α-stimulated PC-3U cells. Similar results were obtained in the mouse macrophage cell line RAW264.7 after LPS treatment. In conclusion, polyubiquitination of TAK1 is correlated with activation of TAK1 and is essential for activation of NF-κB signaling downstream of several receptors.
authors: Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
authors: Anahita
authors: A
authors: Hamidi
authors: Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
authors: Verena
authors: V
authors: von Bulow
authors: Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
authors: Rosita
authors: R
authors: Hamidi
authors: Organic and Bioorganic Laboratory, University of Strasbourg, CNRS (UMR7006), Strasbourg, France.
authors: Nicolas
authors: N
authors: Winssinger
authors: Organic and Bioorganic Laboratory, University of Strasbourg, CNRS (UMR7006), Strasbourg, France.
authors: Sofia
authors: S
authors: Barluenga
authors: Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
authors: Carl-Henrik
authors: CH
authors: Heldin
authors: Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden; Medical Biosciences, Umeå University, 90185 Umeå, Sweden. Electronic address: marene.landstrom@medbio.umu.se.
authors: Marene
authors: M
authors: Landström
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D019943:Amino Acid Substitution; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D008239:Lysine; D020930:MAP Kinase Kinase Kinases; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C495345:TLR4 protein, human