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.
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DOI：
10.1371/journal.pgen.1009275
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发表时间：
2021-04
期刊：
影响因子：
4.5
通讯作者：
Ditzel M
中科院分区：
文献类型：
--
作者：
Mellis D;Staines KA;Peluso S;Georgiou IC;Dora N;Kubiak M;Van't Hof R;Grillo M;Farquharson C;Kinsella E;Thornburn A;Ralston SH;Salter DM;Riobo-Del Galdo NA;Hill RE;Ditzel M
哺乳动物Hedgehog（HH）信号通路在组织稳态中起重要作用，其失调与风湿性疾病有关。UBR 5是E3泛素蛋白连接酶Hyd的哺乳动物同源物，Hyd是果蝇中Hh途径的负调节因子。为了研究UBR 5通过调节哺乳动物HH信号在肌肉骨骼系统调节中的可能作用，我们建立了一个肢芽间充质中UBR 5功能特异性丧失的小鼠模型。我们的发现揭示了UBR 5在维持软骨稳态和抑制化生中的作用。ubr 5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。基因抑制smoothened（Smo），HH信号传导的关键介质，显着增强Ubr5突变体表型。HH信号在小鼠和细胞模型系统的分析表明，Ubr5刺激经典HH信号的损失，同时也增加PKA活性。此外，人类骨关节炎样本揭示了UBR 5表达、经典HH信号传导和PKA活性标志物之间的相似相关性。我们的研究确定了Ubr5基因在维持骨骼组织稳态中的关键功能和HH信号通路的意想不到的调节模式。泛素连接酶修饰蛋白质后，这是必不可少的各种细胞过程。UBR 5是E3泛素连接酶，在果蝇中是Hedgehog信号传导的调节剂。在哺乳动物中，Hedgehog（HH）信号通路在许多其他作用中，在组织维持中起着至关重要的作用，这一过程称为稳态。开发了一种小鼠遗传系统，以特异性地消除胚胎肢体组织中的UBR 5功能，随后形成骨骼和结缔组织（韧带和肌腱）。这种方法揭示了UBR 5作为正常软骨和骨过度生长的有效抑制剂，并防止膝盖和踝关节附近结缔组织中异位部位的骨形成。与异常生长相反，UBR 5抑制缓冲膝关节的关节软骨的降解，导致底层骨的广泛暴露。此外，UBR 5与HH通路的一个组分smoothened相互作用，将UBR 5鉴定为出生后肌肉骨骼系统中哺乳动物HH信号传导的调节剂。总之，这项工作表明，UBR 5与HH通路相互作用，以调节腿部关节内和关节周围的骨骼稳态，并确定了可用于生物医学工程和临床应用的靶点。
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 in Drosophila. 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 of Ubr5 function in limb bud mesenchyme. Our findings revealed a role for UBR5 in maintaining cartilage homeostasis and suppressing metaplasia. Ubr5 loss 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 the Ubr5 mutant phenotype. Analysis of HH signalling in both mouse and cell model systems revealed that loss of Ubr5 stimulated canonical HH-signalling while also increasing PKA activity. In addition, human osteoarthritic samples revealed similar correlations between UBR5 expression, canonical HH signalling and PKA activity markers. Our studies identified a crucial function for the Ubr5 gene in the maintenance of skeletal tissue homeostasis and an unexpected mode of regulation of the HH signalling pathway. Ubiquitin ligases modify proteins post-translationally which is essential for a variety of cellular processes. UBR5 is an E3 ubiquitin ligase and in Drosophila is a regulator of Hedgehog signaling. In mammals, the Hedgehog (HH) signalling pathway, among many other roles, plays an essential role in tissue maintenance, a process called homeostasis. A murine genetic system was developed to specifically eliminate UBR5 function from embryonic limb tissue that subsequently forms bone and connective tissue (ligaments and tendons). This approach revealed that UBR5 operates as a potent suppressor of excessive growth of normal cartilage and bone and prevents formation of bone in ectopic sites in connective tissue near the knees and ankle joints. In contrast to abnormal growth, UBR5 inhibits degradation of the articular cartilage that cushions the knee joint leading to extensive exposure of underlying bone. Furthermore, Ubr5 interacts with smoothened, a component of the HH pathway, identifying UBR5 as a regulator of mammalian HH signaling in the postnatal musculoskeletal system. In summary, this work shows that UBR5 interacts with the HH pathway to regulate skeletal homeostasis in and around joints of the legs and identifies targets that may be harnessed for biomedical engineering and clinical applications.
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