FBXL13 directs the proteolysis of CEP192 to regulate centrosome homeostasis and cell migration
FBXL13 directs the proteolysis of CEP192 to regulate centrosome homeostasis and cell migration
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DOI：
10.15252/embr.201744799
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发表时间：
2018-03-01
期刊：
影响因子：
7.7
通讯作者：
D'Angiolella, Vincenzo
中科院分区：
文献类型：
--
作者：
Fung, Ella;Richter, Carmen;D'Angiolella, Vincenzo
异常的中心体组织与随之而来的微管成核能力的改变，使肿瘤细胞增殖和入侵，尽管增加基因组的不稳定性。CEP 192是中心体复制起始过程和控制中心体微管成核的关键因子。然而，CEP 192的调控手段仍然未知。在这里，我们报告说，FBXL 13，SCF（SKP 1-CUL 1-F-box）-家族E3泛素连接酶的结合决定簇，是在中心体富集，并与中心体蛋白质Centrin-2，Centrin-3，CEP 152和CEP 192相互作用。其中，CEP 192是FBXL 13蛋白酶体降解的特异性靶向分子。因此，诱导的FBXL 13表达下调中心体γ-微管蛋白并破坏中心体微管阵列。此外，FBXL 13的消耗诱导中心体处的高水平的CEP 192和γ-微管蛋白，其结果是细胞运动性缺陷。总之，我们认为FBXL 13是微管成核活性的一种新型调节剂，并强调了在促进细胞运动中的作用，具有潜在的肿瘤促进作用。
Aberrant centrosome organisation with ensuing alterations of microtubule nucleation capacity enables tumour cells to proliferate and invade despite increased genomic instability. CEP192 is a key factor in the initiation process of centrosome duplication and in the control of centrosome microtubule nucleation. However, regulatory means of CEP192 have remained unknown. Here, we report that FBXL13, a binding determinant of SCF (SKP1-CUL1-F-box)-family E3 ubiquitin ligases, is enriched at centrosomes and interacts with the centrosomal proteins Centrin-2, Centrin-3, CEP152 and CEP192. Among these, CEP192 is specifically targeted for proteasomal degradation by FBXL13. Accordingly, induced FBXL13 expression downregulates centrosomal gamma-tubulin and disrupts centrosomal microtubule arrays. In addition, depletion of FBXL13 induces high levels of CEP192 and gamma-tubulin at the centrosomes with the consequence of defects in cell motility. Together, we characterise FBXL13 as a novel regulator of microtubule nucleation activity and highlight a role in promoting cell motility with potential tumour-promoting implications.