Abstract
Upon activation, TGF-β type I receptor (TβRI) undergoes active ubiquitination via recruitment of E3 ligases to the receptor complex by Smad7. However, how ubiquitination of TβRI is coupled to intracellular trafficking, and protein degradation remains unclear. We report here that Tollip, an adaptor protein that contains both ubiquitin-associated domains and endosome-targeting domain, plays an important role in modulating trafficking and degradation of TβRI. Tollip was previously demonstrated to possess a functional role in modulating the signaling of interleukin-1 and Toll-like receptors. We identify here that Tollip interacts with Smad7, a major modulatory protein involved in the negative regulation of TGF-β signaling. Overexpression of Tollip antagonizes TGF-β-stimulated transcriptional response, Smad2 phosphorylation, and epithelial-mesenchymal transition. Tollip also interacts with ubiquitinated TβRI, and such interaction requires ubiquitin-associated domains of Tollip. The interaction and intracellular colocalization of Tollip with TβRI is enhanced by Smad7. Overexpression of Tollip accelerates protein degradation of activated TβRI. In addition, Tollip alters subcellular compartmentalization and endosomal trafficking of activated TβRI. Collectively, our studies reveal that Tollip cooperates with Smad7 to modulate intracellular trafficking and degradation of ubiquitinated TβRI, whereby negatively regulates TGF-β signaling pathway.
Highlights
How TGF- signaling pathway is modulated by intracellular trafficking is not fully understood
We identify here that Tollip interacts with Smad7, a major modulatory protein involved in the negative regulation of TGF- signaling
The duration and intensity of TGF- signaling is precisely controlled at different levels from ligand availability and receptor stability to Smads activity [30]
Summary
How TGF- signaling pathway is modulated by intracellular trafficking is not fully understood. We report here that Tollip, an adaptor protein that contains both ubiquitin-associated domains and endosome-targeting domain, plays an important role in modulating trafficking and degradation of TRI. Our studies reveal that Tollip cooperates with Smad to modulate intracellular trafficking and degradation of ubiquitinated TRI, whereby negatively regulates TGF- signaling pathway. Smad antagonizes TGF- signaling through multiple mechanisms, such as by interfering with the recruitment of receptorrestrictive Smads into the type I receptor upon ligand activation [4] by inducing degradation of TRI receptor via recruitment of E3 ubiquitin ligases such as Smurfs [5, 6] and by recruiting protein phosphatase 1 (PP1) to the receptor complex [7]. The lipid-raft-mediated caveolar internalization contains the Smad7-Smurf complex and facilitates receptor degradation [9]
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