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EMBO Reports:中科院生化细胞所赵允博狗官方网站揭示Hh信号通路转录因子Ci/Gli蛋白稳定性调控新机制

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摘要 : 2017年9月8日,欧洲分子博狗官方网站首页学杂志《EMBO Reports》杂志上在线发表了中国科学院博狗官方网站首页化学与细胞博狗官方网站首页学研究所赵允博狗官方网站的最新研究成果 “UbcD1 regulates Hedgehog signaling by directly modulating Ci ubiquitination and processing”。
2017年9月8日,欧洲分子博狗官方网站首页学杂志《EMBO Reports》杂志上在线发表了中国科学院博狗官方网站首页化学与细胞博狗官方网站首页学研究所赵允博狗官方网站的最新研究成果 “UbcD1 regulates Hedgehog signaling by directly modulating Ci ubiquitination and processing”。研究发现UbcD1调控了Hh信号通路中关键转录因子Ci/Gli的蛋白稳定性。潘晨宇博士为论文第一作者,赵允研究员为论文通讯作者。 Hh信号通路在胚胎发育、成体组织稳态维持以及肿瘤的发生发展中起着重要作用。Hh信号通路的异常会引发多种严重的人类疾病,包括一些出生缺陷和癌症。转录因子Ci/Gli的活性受到了多种翻译后修饰严格的调控,其中泛素化介导的蛋白酶体降解直接调控了Ci/Gli的稳定性及蛋白水平,因此对于Hh信号通路的活性水平具有重要的调控作用。在Hh信号通路中,存在两种较为重要的泛素化调控手段。当没有Hh信号时,由Slimb-Cul1 E3 ligase介导Ci/Gli泛素化进而发生选择性部分降解;当存在高浓度Hh信号时,则由Rdx-Cul3 E3 ligase介导Ci/Gli泛素化进而发生完全降解。赵允博狗官方网站前期的研究发现,在Ci/Gli选择性降解过程中,Ter94 ATPase复合物、UB的赖氨酸K11泛素链以及Sqh分子对于介导Ci/Gli发生选择性部分降解是非常重要的(Dev Cell, 2013; J Mol Cell Biol, 2015),而同时去泛素化酶Usp7也通过调控泛素化水平参与了Ci/Gli的稳定性调控(Dev Cell, 2015)。然而,对于Ci/Gli的选择性降解过程中泛素化E2酶(ubiquitin-conjugating enzyme)是否具有特异性以及是否在决定泛素链种类过程中发挥作用还处于未知阶段。 研究中,赵允博狗官方网站的潘晨宇博士通过遗传学筛选发现E2--UbcD1调控了Ci/Gli的蛋白稳定性,并且特异性地参与Slimb-Cul1 E3 ligase介导的Ci泛素化降解过程,而在Rdx-Cul3 E3 ligase介导的Ci/Gli泛素化降解过程中不起作用。UbcD1在Ci/Gli的泛素化降解过程中也参与了K-11泛素链的形成。同时,这一调控机制在脊椎动物中高度保守。这一工作进一步揭示了Hh通路转录因子Ci/Gli的稳定调控机制,也提供了一个针对Ci/Gli降解调控的潜在药物靶点。 EMBO Reports:中科院生化细胞所赵允博狗官方网站揭示Hh信号通路转录因子Ci/Gli蛋白稳定性调控新机制
Ubiquitylation of Ci/Gli is known to regulate Hh signaling. This study identifies UbcD1 as the ubiquitin‐conjugating E2 enzyme responsible for Slimb‐Cul1 E3 ligase‐mediated partial degradation of Ci/Gli – a function that is conserved in metazoans.
1. UbcD1 is a new regulator of Hh signaling and Gli/Ci processing. 2. UbcD1 is a critical E2 essential for Slimb‐mediated Ci partial degradation by adding both K11‐ and K48‐linked poly‐ubIQuitin chains to Ci. 3. The function of UbcD1 in repressing Hh pathway and modulating Ci/Gli stABIlity is conserved in metazoans. 原文链接: UbcD1 regulates Hedgehog signaling by directly modulating Ci ubiquitination and processing 原文摘要: The Hh pathway controls many morphogenetic processes in metazoans and plays important roles in numerous pathologies and in cancer. Hh signaling is mediated by the activity of the Gli/Ci family of transcription factors. Several studies in Drosophilahave shown that ubiquitination by the ubiquitin E3 ligases Slimb and Rdx(Hib) plays a crucial role in controlling Ci stability dependent on the levels of Hh signals. If Hh levels are low, Slimb adds K11‐ and K48‐linked poly‐ubiquitin chains on Ci resulting in partial degradation. Ubiquitin E2 enzymes are pivotal in determining the topologies of ubiquitin chains. However, which E2 enzymes participate in the selective ubiquitination‐degradation of Ci remains elusive. Here, we find that the E2 enzyme UbcD1 negatively regulates Hh signaling activity in Drosophila wing disks. Genetic and biochemical analyses in wing disks and in cultured cells reveal that UbcD1 directly controls Ci stability. Interestingly, UbcD1 is found to be selectively involved in Slimb‐mediated Ci degradation. Finally, we show that the homologs of UbcD1 play a conserved role in modulating Hh signaling in vertebrates. DOI:10.15252/embr.201643289 作者:赵允 点击:
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