Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ
Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ
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DOI：
10.1093/hmg/ddy322
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发表时间：
2019-01-01
影响因子：
3.5
通讯作者：
Caplan, Michael J.
中科院分区：
文献类型：
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作者：
Merrick, David;Mistry, Kavita;Caplan, Michael J.
多囊蛋白-1（PC1）由常染色体显性遗传性多囊肾病中突变的PKD1基因编码，调节包括骨发育在内的许多过程。控制成骨细胞分化的转录因子RunX2的活性在Pkd1突变小鼠中降低，但控制RunX2的PC 1激活的机制尚不清楚。PC1经过调节切割，释放其C-末端尾（CTT），其易位到细胞核，以调节参与增殖和凋亡的转录途径。我们发现，PC1的裂解CTT（PC1-CTT）刺激转录辅激活因子TAZ（Wwtr1），RunX2的必需辅激活因子。PC1-CTT与TAZ物理相互作用，以TAZ依赖性方式刺激前成骨细胞中的RunX2转录活性。PC1-CTT增加了TAZ和RunX2之间的相互作用，并增强了p300转录共调节蛋白向TAZ/RunX2/PC1-CTT复合物的募集。注射针对pkd1的吗啉代的斑马鱼表现出严重的骨钙化缺陷和卷曲尾表型。将编码PC 1-CTT的信使RNA（mRNA）注射到pkd 1-morphant鱼中可以恢复骨矿化并降低卷尾表型的严重程度。这些作用通过共同注射针对TAZ的吗啉代来消除。注射编码显性活性TAZ构建体的mRNA足以拯救在PKD1-吗啉代处理的鱼中观察到的卷曲尾表型和骨骼缺陷。因此，TAZ构成了PC 1介导其生理功能的关键机制环节。
Polycystin-1 (PC1), encoded by the PKD1 gene that is mutated in the autosomal dominant polycystic kidney disease, regulates a number of processes including bone development. Activity of the transcription factor RunX2, which controls osteoblast differentiation, is reduced in Pkd1 mutant mice but the mechanism governing PC1 activation of RunX2 is unclear. PC1 undergoes regulated cleavage that releases its C-terminal tail (CTT), which translocates to the nucleus to modulate transcriptional pathways involved in proliferation and apoptosis. We find that the cleaved CTT of PC1 (PC1-CTT) stimulates the transcriptional coactivator TAZ (Wwtr1), an essential coactivator of RunX2. PC1-CTT physically interacts with TAZ, stimulating RunX2 transcriptional activity in pre-osteoblast cells in a TAZ-dependent manner. The PC1-CTT increases the interaction between TAZ and RunX2 and enhances the recruitment of the p300 transcriptional co-regulatory protein to the TAZ/RunX2/PC1-CTT complex. Zebrafish injected with morpholinos directed against pkd1 manifest severe bone calcification defects and a curly tail phenotype. Injection of messenger RNA (mRNA) encoding the PC1-CTT into pkd1-morphant fish restores bone mineralization and reduces the severity of the curly tail phenotype. These effects are abolished by co-injection of morpholinos directed against TAZ. Injection of mRNA encoding a dominant-active TAZ construct is sufficient to rescue both the curly tail phenotype and the skeletal defects observed in pkd1-morpholino treated fish. Thus, TAZ constitutes a key mechanistic link through which PC1 mediates its physiological functions.