USP15 靶向 ALK3/BMPR1A 进行去泛素化以增强骨形态发生蛋白信号传导。
USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling.
机构信息
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dow St., Dundee DD1 5EH, UK.
Division of Systems Biology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill NW7 1AA, UK.
出版信息
Open Biol. 2014 May;4(5):140065. doi: 10.1098/rsob.140065.
Protein kinase ALK3/BMPR1A mediates bone morphogenetic protein (BMP) signalling through phosphorylation and activation of SMADs 1/5/8. SMAD6, a transcriptional target of BMP, negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin-mediated degradation. Here, we identify a deubiquitylating enzyme USP15 as an interactor of SMAD6 and ALK3. We show that USP15 enhances BMP-induced phosphorylation of SMAD1 by interacting with and deubiquitylating ALK3. RNAi-mediated depletion of USP15 increases ALK3 K48-linked polyubiquitylation, and reduces both BMP-induced SMAD1 phosphorylation and transcription of BMP target genes. We also show that loss of USP15 expression from mouse myoblast cells inhibits BMP-induced osteoblast differentiation. Furthermore, USP15 modulates BMP-induced phosphorylation of SMAD1 and transcription during Xenopus embryogenesis.
蛋白激酶 ALK3/BMPR1A 通过磷酸化和激活 SMADs 1/5/8 来介导骨形态发生蛋白 (BMP) 信号转导。SMAD6 是 BMP 的转录靶标，通过招募 E3 泛素连接酶并将 ALK3 靶向泛素介导的降解，负调控 BMP 途径。在这里，我们鉴定出一种去泛素化酶 USP15 作为 SMAD6 和 ALK3 的相互作用蛋白。我们表明，USP15 通过与 ALK3 相互作用和去泛素化来增强 BMP 诱导的 SMAD1 磷酸化。RNAi 介导的 USP15 耗竭增加了 ALK3 K48 连接的多泛素化，减少了 BMP 诱导的 SMAD1 磷酸化和 BMP 靶基因的转录。我们还表明，从鼠成肌细胞中缺失 USP15 表达抑制了 BMP 诱导的成骨细胞分化。此外，USP15 在 Xenopus 胚胎发生过程中调节 BMP 诱导的 SMAD1 磷酸化和转录。
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