STIL Microcephaly Mutations Interfere with APC/C-Mediated Degradation and Cause Centriole Amplification
STIL Microcephaly Mutations Interfere with APC/C-Mediated Degradation and Cause Centriole Amplification
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DOI：
10.1016/j.cub.2013.12.016
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发表时间：
2014-02-17
期刊：
影响因子：
9.2
通讯作者：
Nigg, Erich A.
中科院分区：
文献类型：
--
作者：
Arquint, Christian;Nigg, Erich A.
背景资料：STIL是一个中心粒复制因子，定位于原中心粒侧手翻区，STIL突变与常染色体隐性原发性小头畸形（MCPH）相关。过量的STIL触发中心粒扩增，提出了如何STIL水平regulated.Results的问题：使用荧光延时成像，我们确定了一个两步的过程，最终在有丝分裂结束时消除STIL。首先，在核膜破裂时，Cdk 1触发STIL从中心体易位到细胞质。随后，STIL的细胞质体积通过后期促进复合物/环体（APC/C）-蛋白酶体途径降解。我们确定了一个C-末端KEN盒作为STIL降解的关键。值得注意的是，这个KEN框删除MCPH突变体的STIL，使STIL抗蛋白酶体降解，并造成中心粒amplification.Conclusions：我们的研究结果揭示了Cdk 1在STIL解离的作用，从中心体在早期有丝分裂，与车轮拆卸的时间的影响。此外，我们认为STIL稳定化引发的中心粒扩增是具有相应STIL突变的人类患者小头畸形的根本原因。
Background: STIL is a centriole duplication factor that localizes to the procentriolar cartwheel region, and mutations in STIL are associated with autosomal recessive primary microcephaly (MCPH). Excess STIL triggers centriole amplification, raising the question of how STIL levels are regulated.Results: Using fluorescence time-lapse imaging, we identified a two-step process that culminates in the elimination of STIL at the end of mitosis. First, at nuclear envelope breakdown, Cdk1 triggers the translocation of STIL from centrosomes to the cytoplasm. Subsequently, the cytoplasmic bulk of STIL is degraded via the anaphase-promoting complex/cyclosome (APC/C)-proteasome pathway. We identify a C-terminal KEN box as critical for STIL degradation. Remarkably, this KEN box is deleted in MCPH mutants of STIL, rendering STIL resistant to proteasomal degradation and causing centriole amplification.Conclusions: Our results reveal a role for Cdk1 in STIL dissociation from centrosomes during early mitosis, with implications for the timing of cartwheel disassembly. Additionally, we propose that centriole amplification triggered by STIL stabilization is the underlying cause of microcephaly in human patients with corresponding STIL mutations.