Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
EMBO J. 2011 Oct 21;30(23):4790-804. doi: 10.1038/emboj.2011.378.
Centriole duplication involves the growth of a procentriole next to the parental centriole. Mutations in STIL and CPAP/CENPJ cause primary microcephaly (MCPH). Here, we show that human STIL has an asymmetric localization to the daughter centriole and is required for procentriole formation. STIL levels oscillate during the cell cycle. Interestingly, STIL interacts directly with CPAP and forms a complex with hSAS6. A natural mutation of CPAP (E1235V) that causes MCPH in humans leads to significantly lower binding to STIL. Overexpression of STIL induced the formation of multiple procentrioles around the parental centriole. STIL depletion inhibited normal centriole duplication, Plk4-induced centriole amplification, and CPAP-induced centriole elongation, and resulted in a failure to localize hSAS6 and CPAP to the base of the nascent procentriole. Furthermore, hSAS6 depletion hindered STIL targeting to the procentriole, implying that STIL and hSAS6 are mutually dependent for their centriolar localization. Together, our results indicate that the two MCPH-associated proteins STIL and CPAP interact with each other and are required for procentriole formation, implying a central role of centriole biogenesis in MCPH.
中心体复制涉及到旁准生体在亲代中心体旁边的生长。STIL 和 CPAP/CENPJ 的突变会导致原发性小头畸形 (MCPH)。在这里，我们表明人类 STIL 具有向子中心体的不对称定位，并且是生成立方体所必需的。STIL 水平在细胞周期中波动。有趣的是，STIL 与 CPAP 直接相互作用，并与 hSAS6 形成复合物。CPAP 的一种自然突变 (E1235V) 导致人类 MCPH，导致与 STIL 的结合显著降低。STIL 的过表达诱导了亲代中心体周围多个生成立方体的形成。STIL 耗竭抑制了正常的中心体复制、Plk4 诱导的中心体扩增和 CPAP 诱导的中心体伸长，并导致 hSAS6 和 CPAP 无法定位到新生成的生成立方体的基部。此外，hSAS6 的耗竭阻碍了 STIL 向生成立方体的靶向，这意味着 STIL 和 hSAS6 相互依赖于它们的中心体定位。总之，我们的结果表明，两种与 MCPH 相关的蛋白 STIL 和 CPAP 相互作用，并且是生成立方体所必需的，这表明中心体发生在 MCPH 中起着核心作用。
