The human microcephaly protein STIL interacts with CPAP and is required for procentriole formation

• Published in: The EMBO journal Vol. 30; no. 23; pp. 4790 - 4804
• Main Authors: Tang, Chieh-Ju C, Lin, Shin-Yi, Hsu, Wen-Bin, Lin, Yi-Nan, Wu, Chien-Ting, Lin, Yu-Chih, Chang, Ching-Wen, Wu, Kuo-Sheng, Tang, Tang K
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 30.11.2011; Nature Publishing Group UK; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Animals; biogenesis; Cattle; Cell cycle; Cell Cycle - physiology; Cell Cycle Proteins - metabolism; Cell Division - physiology; Cells, Cultured; Centrioles - genetics; Centrioles - metabolism; Centrioles - pathology; centrosome duplication; EMBO05; EMBO06; HEK293 Cells; HeLa Cells; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; MCPH; microcephaly; Microcephaly - genetics; Microcephaly - physiopathology; Microscopy, Confocal; Microscopy, Fluorescence; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mutation; procentriole formation; Protein Binding; Proteins; microcephaly; procentriole formation; biogenesis; MCPH; centrosome duplication; cell cycle
• ISSN: 0261-4189; 1460-2075
• 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. Several genes mutated in human primary microcephaly encode key centrosome proteins. STIL/MCPH7 now joins this cast, with centriole biogenesis roles similar to those played by its distant relatives CeSAS‐5/DmAna2 in invertebrates.