USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110.
USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110.
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中心体复制对细胞分裂至关重要，如果复制不限于每个细胞周期的单轮，则可能导致基因组不稳定。中心体复制部分由CP 110控制，CP 110是一种中心粒蛋白，其积极调节中心粒复制，同时限制中心粒延伸和纤毛发生。维持正常的CP 110水平是必不可少的，因为过量的CP 110驱动中心体过度复制并抑制纤毛发生，而其消耗抑制中心粒扩增并导致高度伸长的中心粒和生长细胞中纤毛的异常组装。CP 110水平部分通过SCF细胞周期蛋白F介导的细胞周期G2和M期的泛素化而受到严格控制。在这里，我们报告了一个新的机制，调节中心体复制，需要USP 33，去泛素化酶（DUB）能够调节CP 110水平。USP 33与CP 110相互作用并主要在S和G2/M期定位于中心粒，在此期间中心粒复制和伸长。USP 33有效且特异性地去泛素化CP 110，但不去其他细胞周期蛋白F底物。USP 33活性拮抗SCF细胞周期蛋白F介导的泛素化并促进额外中心粒病灶的产生，而USP 33的消融使CP 110不稳定，从而抑制中心体扩增和有丝分裂缺陷。据我们所知，这些研究已经确定了第一个中心粒去泛素化酶，其表达调节中心体稳态通过对抗细胞周期蛋白F介导的破坏的关键底物，并建议潜在的治疗策略，抑制肿瘤发生与中心体扩增。
Centrosome duplication is critical for cell division, and genome instability can result if duplication is not restricted to a single round per cell cycle. Centrosome duplication is controlled in part by CP110, a centriolar protein that positively regulates centriole duplication while restricting centriole elongation and ciliogenesis. Maintenance of normal CP110 levels is essential, since excessive CP110 drives centrosome over-duplication and suppresses ciliogenesis, whereas its depletion inhibits centriole amplification and leads to highly elongated centrioles and aberrant assembly of cilia in growing cells. CP110 levels are tightly controlled in part through SCFcyclin F-mediated ubiquitylation during G2 and M phase of the cell cycle. Here we report a new mechanism for regulation of centrosome duplication that requires USP33, a de-ubiquitylating enzyme (DUB) able to regulate CP110 levels. USP33 interacts with CP110 and localizes to centrioles primarily during S and G2/M phase, the period during which centrioles duplicate and elongate. USP33 potently and specifically de-ubiquitylates CP110, but not other cyclin F substrates. USP33 activity antagonizes SCFcyclin F-mediated ubiquitylation and promotes generation of supernumerary centriolar foci, whereas ablation of USP33 destabilizes CP110 and thereby inhibits centrosome amplification and mitotic defects. To our knowledge, these studies have identified the first centriolar de-ubiquitinating enzyme whose expression regulates centrosome homeostasis by countering cyclin F-mediated destruction of a key substrate and suggest potential therapeutic strategies for inhibiting tumorigenesis associated with centrosome amplification.
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