USP15 is a deubiquitylating enzyme for receptor-activated SMADs

Abstract

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 recognition. Several ubiquitin ligases serve as inhibitors of R-SMADs, 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 degradation. 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.

Deubiquitylases From Genes to Organism

“…However, it has also been shown that USP15 empowers transcriptional activation of R-SMADs, the ultimate effectors of the TGF-␤ pathway, by removing inactivating monoubiquitin (104); so fully discriminating the physiological importance of each of these effects may prove challenging. One consideration is that USP15 also promotes bone morphogenic protein (BMP) signaling, which utilizes overlapping SMAD family members with the TGF-␤ pathway, as effectors of an entirely distinct receptor type (104). USP11 was also identified as the major SMAD7 interacting DUB by proteomics and is proposed to be recruited to TGF-␤ receptor, which it deubiquitylates, in a similar manner to USP15 (6).…”

The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes

“…SMAD1/5/8 and SMAD2/3 activation was measured by using pGL3-BMPresponsive element (BRE)-Luc and the pGL3-CAGA-Luc plasmids, respectively. 16 …”

Signaling Receptors for TGF-β Family Members

“…Interestingly, the USP15 gene was found to be amplified in glioblastoma, breast cancer, and ovarian cancer, suggesting that enhanced TGFb signaling, as a consequence of USP15 overactivity, promotes progression of these tumors. USP15 has also been found to deubiquitylate monoubiquitylated R-Smads, promoting Smad activity (Inui et al 2011). In addition, USP11 has been shown to deubiquitylate TbRI and to enhance TGF-b signaling (Al-Salihi et al 2012).…”