Transmembrane anterior posterior transformation 1 regulates BMP signaling and modulates the protein stability of SMAD1/5.
Transmembrane anterior posterior transformation 1 regulates BMP signaling and modulates the protein stability of SMAD1/5.
复制标题
跨膜前后转换 1 调节 BMP 信号传导并调节 SMAD1/5 的蛋白质稳定性
DOI：
10.1016/j.jbc.2022.102684
复制
发表时间：
2022-12
影响因子：
4.8
通讯作者：
Rong, Xiaozhi
中科院分区：
文献类型：
--
作者：
Wang, Bo;Zhao, Qian;Gong, Xiaoxia;Wang, Caixia;Bai, Yan;Wang, Hongying;Zhou, Jianfeng;Rong, Xiaozhi
骨形态发生蛋白(BMP)信号通路在胚胎发育和成体动态平衡的各种生物学过程中起着关键作用。跨膜前后部转化蛋白1(TAPT1)是一种进化上保守的蛋白，参与了小鼠的轴向骨骼构型。TAPT1基因缺陷导致复杂的致死性骨软骨发育不良。然而，TAPT1的具体细胞活性尚不清楚。在这里，我们报道TAPT1通过促进Smad1/5蛋白与SMURF1 E3泛素连接酶的相互作用而抑制BMP信号转导并破坏Smad1/5蛋白的稳定性，从而导致Smad1/5蛋白酶体的降解。此外，我们还发现BMP信号通路的激活促进了TAPT1的再分布，促进了TAPT1与Smad1的结合。TAPT1缺陷的小鼠C2C12成肌细胞或C3H/10T1/2间充质干细胞表现出Smad1/5/9蛋白水平升高，从而放大BMP的激活，进而促进这些不同的TAPT1缺陷细胞系向成熟成骨细胞的转分化或分化过程。此外，在体内异位成骨模型中观察了TAPT1缺陷对C3H/10T1/2细胞成骨分化的促进作用。重要的是，在患有致死性骨骼发育不良的人类中发现的TAPT1突变的子集在Smad1蛋白水平上表现出功能增强活性。因此，这一发现阐明了TAPT1在调节Smad1/5蛋白稳定性以控制BMP信号转导中的作用。
The bone morphogenetic protein (BMP) signaling pathway plays pivotal roles in various biological processes during embryogenesis and adult homeostasis. Transmembrane anterior posterior transformation 1 (TAPT1) is an evolutionarily conserved protein involved in murine axial skeletal patterning. Genetic defects in TAPT1 result in complex lethal osteochondrodysplasia. However, the specific cellular activity of TAPT1 is not clear. Herein, we report that TAPT1 inhibits BMP signaling and destabilizes the SMAD1/5 protein by facilitating its interaction with SMURF1 E3 ubiquitin ligase, which leads to SMAD1/5 proteasomal degradation. In addition, we found that the activation of BMP signaling facilitates the redistribution of TAPT1 and promotes its association with SMAD1. TAPT1-deficient murine C2C12 myoblasts or C3H/10T1/2 mesenchymal stem cells exhibit elevated SMAD1/5/9 protein levels, which amplifies BMP activation, in turn leading to a boost in the transdifferentiation or differentiation processing of these distinct TAPT1-deficient cell lines changing into mature osteoblasts. Furthermore, the enhancing effect of TAPT1 deficiency on osteogenic differentiation of C3H/10T1/2 cells was observed in an in vivo ectopic bone formation model. Importantly, a subset of TAPT1 mutations identified in humans with lethal skeletal dysplasia exhibited gain-of-function activity on SMAD1 protein levels. Thus, this finding elucidates the role of TAPT1 in the regulation of SMAD1/5 protein stability for controlling BMP signaling.
登录
查看更多内容
影响因子：
16.6
作者：
Guglielmi L;Heliot C;Kumar S;Alexandrov Y;Gori I;Papaleonidopoulou F;Barrington C;East P;Economou AD;French PMW;McGinty J;Hill CS
通讯作者：
Hill CS
影响因子：
7.2
作者：
Katagiri, Takenobu;Watabe, Tetsuro
通讯作者：
Watabe, Tetsuro
DOI：
10.1016/s0006-291x(05)80208-6
发表时间：
1990-10-15
影响因子：
3.1
作者：
KATAGIRI, T;YAMAGUCHI, A;SUDA, T
通讯作者：
SUDA, T
影响因子：
10.5
作者：
Aragon, Eric;Goerner, Nina;Macias, Maria J.
通讯作者：
Macias, Maria J.
影响因子：
2.5
作者：
KIMMEL, CB;BALLARD, WW;SCHILLING, TF
通讯作者：
SCHILLING, TF