Department of Medical Biotechnologies, Section of Histology and Embryology, University of Padua, viale G. Colombo 3, 35100 Padua, Italy.
Nat Cell Biol. 2011 Sep 25;13(11):1368-75. doi: 10.1038/ncb2346.
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.
TGFβ 途径对于胚胎发育和成人组织稳态至关重要。在配体刺激下，TGFβ 和 BMP 受体磷酸化受体激活的 SMAD（R-SMAD），然后与 SMAD4 结合形成转录复合物，通过特定的 DNA 识别调节基因表达。几种泛素连接酶作为 R-SMAD 的抑制剂，但迄今为止尚未鉴定出这些分子的去泛素化酶（DUB）。这就留下了一个未被探索的可能性，即 R-SMAD 的泛素化是可逆的，并参与调节 SMAD 功能，除了降解。在这里，我们鉴定出 USP15 是 R-SMAD 的 DUB。USP15 是哺乳动物细胞和爪蟾胚胎中 TGFβ 和 BMP 反应所必需的。在生化水平上，USP15 主要反对 R-SMAD 单泛素化，这靶向 R-SMAD 的 DNA 结合域，并阻止启动子识别。因此，USP15 对于 SMAD 复合物占据内源性靶启动子至关重要。这些数据确定了一个额外的控制层，其中泛素系统调节 TGFβ 生物学。
