USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110

Abstract

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 cells1,2. CP110 levels are tightly controlled in part through SCFcyclin F-mediated ubiquitylation during G2 and M phase of the cell cycle3. 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.

Centrobin-mediated Regulation of the Centrosomal Protein 4.1-associated Protein (CPAP) Level Limits Centriole Length during Elongation Stage

“…However, alternatively, it is possible that centrobin has a direct or indirect role in inhibiting the proteasome, which prevents the degradation of ubiquitinated proteins, CPAP in particular, possibly by affecting the deubiquitinase function. For example, the activity of deubiquitinase USP33 has been linked to the regulation of centriole distal end capping protein, CP110 (60). It is possible that deubiquitination of CPAP, before protease degradation in the proteasome, may be dependent on USP33 or similar enzymes, and high levels of centrobin may have a regulatory effect on them, which needs to be investigated in the future.…”

The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells

“…In addition, another deubiquitinase Usp33 has recently been shown to localize at the centrosome by its binding with CP110 and its activity antagonizes SCF cyclinF ubiquitination of CP110 (ref. 58).…”

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

“…Some DUBs have been shown to have important roles in the maintenance of centrosome integrity. USP33 positively regulates centrosome duplication by stabilizing centriolar protein CP110, and USP 33 and CP110 are both upregulated in pancreatic ductal carcinomas 28 in which centrosome amplification is detected. 29 USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis.…”