title: Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling.
abstract: Transforming growth factor-β (TGF-β) is a potent anti-inflammatory cytokine that regulates interleukin-1 receptor and Toll-like receptor (TLR) signalling. Here we show a novel mechanism where TGF-β1-induced K48-linked polyubiquitination and degradation of the adaptor MyD88 protein is dependent on the Smad6 protein, but not Smad7, and mediated by recruitment of the Smad ubiquitin regulator factor proteins, Smurf1 and Smurf2, which have E3-ubiquitin ligase activity. Smurf1 interaction with MyD88 appears to be mediated by Smad6, and Smurf2 interaction by Smurf1. Knockdown of endogenous Smurf1 or Smurf2 by RNA interference significantly suppresses the anti-inflammatory effects of TGF-β1 by preventing lipopolysaccharide-induced NF-κB nuclear translocation, resulting in de-suppression of pro-inflammatory gene expression. Similar effects are observed on the lipoteichoic-acid-induced TLR2 pathway, which is also MyD88-dependent, but not the MyD88-independent TLR3 pathway. Thus, our results suggest that MyD88 degradation driven by the Smad6-Smurf pathway is a novel mechanism for TGF-β1-mediated negative regulation of MyD88-dependent pro-inflammatory signalling.
authors: Department of Biological Sciences, Sungkyunkwan University, Suwon 440-746, Korea.
authors: Youn Sook
authors: YS
authors: Lee
authors: Jin Seok
authors: JS
authors: Park
authors: Jun Hwan
authors: JH
authors: Kim
authors: Su Myung
authors: SM
authors: Jung
authors: Jae Young
authors: JY
authors: Lee
authors: Seong-Jin
authors: SJ
authors: Kim
authors: Seok Hee
authors: SH
authors: Park
mesh_terms: D002460:Cell Line; D006801:Humans; D008856:Microscopy, Fluorescence; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction; D051905:Smad6 Protein / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C497802:SMAD6 protein, human; D051905:Smad6 Protein; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D053773:Transforming Growth Factor beta1; D044767:Ubiquitin-Protein Ligases