USP15 is a deubiquitylating enzyme for receptor-activated SMADs
USP15 is a deubiquitylating enzyme for receptor-activated SMADs
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DOI：
10.1038/ncb2346
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发表时间：
2011-11-01
影响因子：
21.3
通讯作者：
Piccolo, Stefano
中科院分区：
文献类型：
--
作者：
Inui, Masafumi;Manfrin, Andrea;Piccolo, Stefano
TGF β通路对于胚胎发育和成人组织稳态是至关重要的。在配体刺激下，TGF β和BMP受体磷酸化受体激活的SMAD（R-SMAD），然后与SMAD 4结合形成转录复合物，通过特异性DNA识别调节基因表达（1，2）。几种泛素连接酶可作为R-SMAD的抑制剂（3，4），但迄今为止尚未鉴定出这些分子的去泛素化酶（DUB）。这使得R-SMADs的泛素化是可逆的并且除了降解之外还参与调节SMAD功能的可能性尚未探索（5）。在这里，我们将USP 15确定为R-SMAD的DUB。USP 15是哺乳动物细胞和非洲爪蟾胚胎中TGF β和BMP反应所必需的。在生物化学水平上，USP 15主要反对R-SMAD单泛素化，其靶向R-SMAD的DNA结合结构域并阻止启动子识别。因此，USP 15对于SMAD复合物占据内源性靶启动子至关重要。这些数据确定了泛素系统调节TGF β生物学的额外控制层。
The TGF beta pathway is critical for embryonic development and adult tissue homeostasis. On ligand stimulation, TGF beta 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(1,2). Several ubiquitin ligases serve as inhibitors of R-SMADs(3,4), 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 degradation(5). Here we identify USP15 as a DUB for R-SMADs. USP15 is required for TGF beta 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 TGF beta biology.