Department of Cellular and Molecular Physiology, New Haven, CT USA.
Department of Cell Biology, Norcross, GA USA.
Hum Mol Genet. 2019 Jan 1;28(1):16-30. doi: 10.1093/hmg/ddy322.
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.
多囊蛋白 1（PC1）由 PKD1 基因编码，PKD1 基因突变会导致常染色体显性多囊肾病，它调节包括骨发育在内的多种过程。转录因子 RunX2 的活性在 Pkd1 突变小鼠中降低，RunX2 控制成骨细胞分化，但调控 PC1 激活 RunX2 的机制尚不清楚。PC1 经历受调控的切割，释放其 C 端尾巴（CTT），CTT 易位到细胞核，调节参与增殖和凋亡的转录途径。我们发现，PC1 的切割 CTT（PC1-CTT）刺激转录共激活因子 TAZ（Wwtr1），TAZ 是 RunX2 的必需共激活因子。PC1-CTT 与 TAZ 发生物理相互作用，以 TAZ 依赖的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。用针对 pkd1 的 morpholino 注射斑马鱼会导致严重的骨骼钙化缺陷和卷曲尾巴表型。将编码 PC1-CTT 的信使 RNA（mRNA）注射到 pkd1-morphant 鱼中会恢复骨矿化并降低卷曲尾巴表型的严重程度。这些效应被针对 TAZ 的共注射 morpholino 所消除。注射编码显性活性 TAZ 构建体的 mRNA 足以挽救 pkd1-morpholino 处理鱼中观察到的卷曲尾巴表型和骨骼缺陷。因此，TAZ 构成了 PC1 介导其生理功能的关键机制联系。
