Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism.
Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism.
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DOI：
10.1016/j.cell.2011.10.045
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发表时间：
2011-12-09
期刊：
影响因子：
64.5
通讯作者：
Rottapel R
中科院分区：
文献类型：
--
作者：
Levaot N;Voytyuk O;Dimitriou I;Sircoulomb F;Chandrakumar A;Deckert M;Krzyzanowski PM;Scotter A;Gu S;Janmohamed S;Cong F;Simoncic PD;Ueki Y;La Rose J;Rottapel R
切尔鲁贝氏症是一种常染色体显性遗传综合征，以炎症性破坏性骨质损害为特征，导致面部骨骼对称畸形。切尔贝氏症是由Sh3bp2基因突变引起的，Sh3bp2基因编码适配器蛋白3BP2。大多数已发现的3BP2突变位于多肽序列RSPPDG中。小鼠出现过度活跃的骨改建、破骨细胞和以粒单核细胞谱系扩张为特征的全身性炎症。小天使症突变改变3BP2功能的机制仍不清楚。在这里，我们发现，tankyrase是聚(ADP-核糖)聚合酶(PARP)家族的成员，通过在破骨细胞中通过ADP-核糖化和随后的E3-泛素连接酶RNF146泛素化来调节3BP2的稳定性。Cherubism突变使3BP2与tankyrase介导的蛋白质破坏解偶联，导致其稳定并随后导致SRC、SYK和VAV信号通路的过度激活。
Cherubism is an autosomal dominant syndrome characterized by inflammatory destructive bony lesions resulting in symmetrical deformities of the facial bones. Cherubism is caused by mutations in Sh3bp2, the gene that encodes the adaptor protein 3BP2. Most identified mutations in 3BP2 lie within the peptide sequence RSPPDG. A mouse model of cherubism develops hyperactive bone remodelling osteoclasts and systemic inflammation characterized by expansion of the myelomonocytic lineage. The mechanism by which cherubism mutations alter 3BP2 function has remained obscure. Here we show that Tankyrase, a member of the poly(ADP-ribose)polymerase (PARP) family, regulates 3BP2 stability through ADP-ribosylation and subsequent ubiquitylation by the E3-ubiquitin ligase RNF146 in osteoclasts. Cherubism mutations uncouple 3BP2 from Tankyrase-mediated protein destruction, which results in its stabilization and subsequent hyperactivation of the SRC, SYK and VAV signalling pathways.
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影响因子：
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影响因子：
15.9
作者：
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通讯作者：
Rottapel, Robert