USP15 is a deubiquitylating enzyme for receptor-activated SMADs
Author: ["Masafumi Inui","Andrea Manfrin","Anant Mamidi","Graziano Martello","Leonardo Morsut","Sandra Soligo","Elena Enzo","Stefano Moro","Simona Polo","Sirio Dupont","Michelangelo Cordenonsi","Stefano Piccolo"]
Publication: Nature Cell Biology
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Abstract
In the TGFβ pathway, receptor-activated SMADs (R-SMADs) associate with SMAD4 to regulate transcription. Piccolo and colleagues reveal that the deubiquitylase USP15 is required for TGFβ responses by reversing R-SMAD ubiquitylation and thereby promoting the retention of the SMAD complex at promoters. The TGFβ pathway is critical for embryonic development and adult tissue homeostasis. On ligand stimulation, TGFβ and BMP receptors phosphorylate receptor-activated SMADs (R-SMADs), which then associate with SMAD4 to form a transcriptional complex that regulates gene expression through specific DNA recognition1,2. Several ubiquitin ligases serve as inhibitors of R-SMADs3,4, yet no deubiquitylating enzyme (DUB) for these molecules has so far been identified. This has left unexplored the possibility that ubiquitylation of R-SMADs is reversible and engaged in regulating SMAD function, in addition to degradation5. Here we identify USP15 as a DUB for R-SMADs. USP15 is required for TGFβ and BMP responses in mammalian cells and Xenopus embryos. At the biochemical level, USP15 primarily opposes R-SMAD monoubiquitylation, which targets the DNA-binding domains of R-SMADs and prevents promoter recognition. As such, USP15 is critical for the occupancy of endogenous target promoters by the SMAD complex. These data identify an additional layer of control by which the ubiquitin system regulates TGFβ biology.
Cite this article
Inui, M., Manfrin, A., Mamidi, A. et al. USP15 is a deubiquitylating enzyme for receptor-activated SMADs. Nat Cell Biol 13, 1368–1375 (2011). https://doi.org/10.1038/ncb2346
