Fbxl13 regulates centrosome homeostasis and migration through ubiquitin mediated proteolysis

F-box proteins are the variable substrate adaptor subunits of the SCF (Skp1, Cul1, F-box) ubiquitin ligases. The family comprise about 69 members with important roles in cancer pathogenesis and cell proliferation. Among the F-box proteins, Fbxl13 is frequently amplified in several cancer patient cohorts suggesting an important role in promoting cancer pathogenesis. However, the main function of Fbxl13 is unknown and its biochemical mechanism of action remains uncharacterised. Here, we show that Fbxl13 specifically interacts with the centrosomal proteins Centrin-2, Centrin-3, Cep152, and Cep192. Fbxl13 is enriched at the centrosome, where it targets Cep192 for ubiquitin mediated proteolysis. In line with this, Fbxl13 overexpression downregulated centrosomal γ-tubulin, and disrupted centrosomal microtubule arrays. Furthermore, depletion of Fbxl13 in U2OS cells corresponds to defects in centrosome duplication and cell motility. Thus, we propose that Fbxl13 is a novel regulator of centrosome duplication and microtubule nucleation activity, highlighting a potential tumourigenic role of Fbxl13 in promoting cell motility.

F-box蛋白（F-box protein）是SCF（Skp1、Cul1、F-box）泛素连接酶的可变底物衔接亚基。该家族包含约69个成员，在癌症发病机制与细胞增殖过程中发挥关键作用。在F-box蛋白中，Fbxl13在多个癌症患者队列中频繁发生扩增，提示其在促进癌症发生发展中具有重要功能。然而，Fbxl13的核心生理功能尚未明确，其生化作用机制仍未被解析。本研究证实，Fbxl13可与中心体蛋白中心蛋白-2（Centrin-2）、中心蛋白-3（Centrin-3）、Cep152及Cep192特异性相互作用。Fbxl13在中心体处富集，并靶向Cep192进行泛素介导的蛋白水解。与此一致，Fbxl13过表达会下调中心体中的γ-微管蛋白水平，并破坏中心体微管阵列结构。此外，在U2OS细胞中敲低Fbxl13会导致中心体复制异常与细胞运动能力受损。综上，本研究提出Fbxl13是中心体复制与微管成核活性的新型调控因子，揭示了Fbxl13通过促进细胞运动发挥潜在致瘤作用的机制。