Ubiquitin-protein ligase Ubr5 cooperates with Hedgehog signalling to promote skeletal tissue homeostasis
Ubiquitin-protein ligase Ubr5 cooperates with Hedgehog signalling to promote skeletal tissue homeostasis
复制标题
泛素蛋白连接酶 Ubr5 与 Hedgehog 信号协同促进骨骼组织稳态
DOI：
10.1101/2020.12.04.411405
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Mellis D
中科院分区：
文献类型：
--
作者：
Mellis D
哺乳动物Hedgehog （HH）信号通路在组织稳态中起重要作用，其失调与风湿病有关。UBR5是E3泛素蛋白连接酶Hyd的哺乳动物同源物，而E3泛素蛋白连接酶Hyd是果蝇hh通路的负调节因子。为了研究UBR5通过调节哺乳动物HH信号在调节肌肉骨骼系统中的可能作用，我们创建了一个小鼠四肢芽间质中fubr5功能特异性缺失的模型。我们的研究结果揭示了UBR5在维持软骨稳态和抑制化生中的作用。ubr5功能丧失导致进行性和戏剧性的关节软骨退化，增大，形状异常的籽骨和广泛的异位组织化生，与肌腱钙化和滑膜骨化有关。遗传抑制smoothened （Smo）是HH信号传导的关键介质，显著增强了ubr5突变体的表型。小鼠和细胞模型系统中HH信号传导的分析显示，fubr5的缺失刺激了典型的HH信号传导，同时也增加了PKA活性。此外，人类骨关节炎样本显示，ubr5表达、典型HH信号和PKA活性标志物之间存在类似的相关性。我们的研究确定了ubr5基因在维持骨组织稳态和HH信号通路的意想不到的调节模式中的关键功能。
Mammalian Hedgehog (HH) signalling pathway plays an essential role in tissue homeostasis and its deregulation is linked to rheumatological disorders. UBR5 is the mammalian homologue of the E3 ubiquitin-protein ligase Hyd, a negative regulator of the Hh-pathway inDrosophila. To investigate a possible role of UBR5 in regulation of the musculoskeletal system through modulation of mammalian HH signaling, we created a mouse model for specific loss ofUbr5function in limb bud mesenchyme. Our findings revealed a role for UBR5 in maintaining cartilage homeostasis and suppressing metaplasia.Ubr5loss of function resulted in progressive and dramatic articular cartilage degradation, enlarged, abnormally shaped sesamoid bones and extensive heterotopic tissue metaplasia linked to calcification of tendons and ossification of synovium. Genetic suppression of smoothened (Smo),a key mediator of HH signalling, dramatically enhanced theUbr5mutant phenotype. Analysis of HH signalling in both mouse and cell model systems revealed that loss ofUbr5stimulated canonical HH-signalling while also increasing PKA activity. In addition, human osteoarthritic samples revealed similar correlations betweenUBR5expression, canonical HH signalling and PKA activity markers. Our studies identified a crucial function for theUbr5gene in the maintenance of skeletal tissue homeostasis and an unexpected mode of regulation of the HH signalling pathway.