Smad6 inhibits non-canonical TGF-β1 signalling by recruiting the deubiquitinase A20 to TRAF6

• Published in: Nature communications 2013-10, Vol.4 (1), p.2562-2562, Article 2562
• Main Authors: Jung, Su Myung, Lee, Ji-Hyung, Park, Jinyoung, Oh, Young Sun, Lee, Sung Kyun, Park, Jin Seok, Lee, Youn Sook, Kim, Jun Hwan, Lee, Jae Young, Bae, Yoe-Sik, Koo, Seung-Hoi, Kim, Seong-Jin, Park, Seok Hee
• Format: Article
• Language: English
• Subjects: 631/80/82/23; 631/80/86; Animals; Apoptosis; Cysteine Endopeptidases; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epithelial Cells - cytology; Epithelial Cells - metabolism; Gene Expression Regulation; HEK293 Cells; Hepatocytes - cytology; Hepatocytes - metabolism; Humanities and Social Sciences; Humans; Intestines - cytology; Intestines - metabolism; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Liver - cytology; Liver - metabolism; MAP Kinase Kinase 4 - genetics; MAP Kinase Kinase 4 - metabolism; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; Mice; Mice, Inbred C57BL; multidisciplinary; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Primary Cell Culture; Science; Science (multidisciplinary); Signal Transduction - genetics; Smad6 Protein - genetics; Smad6 Protein - metabolism; TNF Receptor-Associated Factor 6 - genetics; TNF Receptor-Associated Factor 6 - metabolism; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Tumor Necrosis Factor alpha-Induced Protein 3; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms3562

Transforming growth factor (TGF)-β, a pivotal cytokine involved in a variety of cellular functions, transmits signals through Smad-dependent canonical and Smad-independent noncanonical pathways. In contrast to the canonical TGF-β pathway, it is unknown how noncanonical TGF-β pathways are negatively regulated. Here we demonstrate that the inhibitory Smad Smad6, but not Smad7, negatively regulates TGF-β1-induced activation of the TRAF6-TAK1-p38 MAPK/JNK pathway, a noncanonical TGF-β pathway. TGF-β1-induced Smad6 abolishes K63-linked polyubiquitination of TRAF6 by recruiting the A20 deubiquitinating enzyme in AML-12 mouse liver cells and primary hepatocytes. In addition, the knockdown of Smad6 or A20 in an animal model or cell culture system maintains TAK1 and p38 MAPK/JNK phosphorylation and increases apoptosis, emphasizing the crucial role of the Smad6-A20 axis in negative regulation of the TGF-β1-TRAF6-TAK1-p38 MAPK/JNK pathway. Therefore, our findings provide insight into the molecular mechanisms underlying negative regulation of noncanonical TGF-β pathways. The cytokine TGF-β signals through canonical, Smad-dependent, and non-canonical, Smad-independent pathways. Jung et al . show that Smad6, an inhibitor of canonical TGF-β signalling, also inhibits a non-canonical pathway by recruiting a deubiquitinase to TRAF6.