FBXL13 directs the proteolysis of CEP192 to regulate centrosome homeostasis and cell migration

Aberrant centrosome organisation with ensuing alterations of microtubule nucleation capacity enables tumour cells to proliferate and invade despite increased genomic instability. CEP192 is a key factor in the initiation process of centrosome duplication and in the control of centrosome microtubule nucleation. However, regulatory means of CEP192 have remained unknown. Here, we report that FBXL13, a binding determinant of SCF (SKP1‐CUL1‐F‐box)‐family E3 ubiquitin ligases, is enriched at centrosomes and interacts with the centrosomal proteins Centrin‐2, Centrin‐3, CEP152 and CEP192. Among these, CEP192 is specifically targeted for proteasomal degradation by FBXL13. Accordingly, induced FBXL13 expression downregulates centrosomal γ‐tubulin and disrupts centrosomal microtubule arrays. In addition, depletion of FBXL13 induces high levels of CEP192 and γ‐tubulin at the centrosomes with the consequence of defects in cell motility. Together, we characterise FBXL13 as a novel regulator of microtubule nucleation activity and highlight a role in promoting cell motility with potential tumour‐promoting implications. Synopsis FBXL13 is a novel centrosomal E3 ubiquitin ligase, which targets CEP192 for ubiquitin‐mediated degradation. By this means, FBXL13 regulates microtubule nucleation activity as well as cell motility with potential tumor‐promoting implications. FBXL13 targets CEP192 for ubiquitin‐mediated proteolysis at centrosomes. Ubiquitylation of CEP192 by FBXL13 organizes the interphase microtubule cytoskeleton. FBXL13 favors cell migration via CEP192 degradation. Graphical Abstract FBXL13 is a novel centrosomal E3 ubiquitin ligase, which targets CEP192 for ubiquitin‐mediated degradation to regulate microtubule nucleation activity as well as cell motility.