Disruption of the basal body comprises proteasomal function and perturbs intracellular Wnt response
Disruption of the basal body comprises proteasomal function and perturbs intracellular Wnt response
复制标题
DOI：
10.1038/ng.2007.12
复制
发表时间：
2007-11-01
期刊：
影响因子：
30.8
通讯作者：
Katsanis, Nicholas
中科院分区：
文献类型：
--
作者：
Gerdes, Jantje M.;Liu, Yangfan;Katsanis, Nicholas
初级纤毛和基体是进化上保守的细胞器，介导细胞内和细胞外环境之间的通信。本研究表明，编码基础体蛋白的bbs1、bbs4和mkks（也称为bbs6）是斑马鱼趋同和扩展所必需的，并与wnt11和wnt5b相互作用。在斑马鱼胚胎和哺乳动物纤毛细胞中，抑制bbs1、bbs4和mkks转录会导致β -连环蛋白的稳定，并伴随t细胞因子（TCF）依赖性转录的上调，这一缺陷通过轴突运动蛋白亚基KIF3A的沉默而不是细胞质微管网络的化学破坏来表现。这些观察结果部分归因于蛋白酶体有缺陷的降解；抑制BBS4导致蛋白酶体靶向紊乱，并伴随细胞质β -连环蛋白的积累。综上所述，我们的数据表明，基底体是通过选择性蛋白质水解来解释Wnt信号的重要调节因子，并表明该系统中的缺陷可能有助于人类纤毛病的表型。
Primary cilia and basal bodies are evolutionarily conserved organelles that mediate communication between the intracellular and extracellular environments. Here we show that bbs1, bbs4 and mkks ( also known as bbs6), which encode basal body proteins, are required for convergence and extension in zebrafish and interact with wnt11 and wnt5b. Suppression of bbs1, bbs4 and mkks transcripts results in stabilization of beta-catenin with concomitant upregulation of T-cell factor ( TCF)-dependent transcription in both zebrafish embryos and mammalian ciliated cells, a defect phenocopied by the silencing of the axonemal kinesin subunit KIF3A but not by chemical disruption of the cytoplasmic microtubule network. These observations are attributable partly to defective degradation by the proteasome; suppression of BBS4 leads to perturbed proteasomal targeting and concomitant accumulation of cytoplasmic beta-catenin. Cumulatively, our data indicate that the basal body is an important regulator of Wnt signal interpretation through selective proteolysis and suggest that defects in this system may contribute to phenotypes pathognomonic of human ciliopathies.