USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110

• Published in: Nature (London) Vol. 495; no. 7440; pp. 255 - 259
• Main Authors: Li, Ji, D’Angiolella, Vincenzo, Seeley, E. Scott, Kim, Sehyun, Kobayashi, Tetsuo, Fu, Wenxiang, Campos, Eric I., Pagano, Michele, Dynlacht, Brian David
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.03.2013; Nature Publishing Group
• Subjects: 631/337/474/2289; 631/80/641; Animals; Cell Cycle; Cell Cycle Proteins - metabolism; Cell Line; Cellular control mechanisms; Centrioles; Centrioles - metabolism; Centrosome - metabolism; Centrosomes; Cyclins - metabolism; Homeostasis; Humanities and Social Sciences; Humans; letter; Microtubule-Associated Proteins - metabolism; multidisciplinary; Neoplasms - pathology; Neoplasms - therapy; Phosphoproteins - metabolism; Physiological aspects; Protein biosynthesis; Protein Stability; Proteins; Science; SKP Cullin F-Box Protein Ligases - metabolism; Tumors; Ubiquitin Thiolesterase - metabolism; Ubiquitination; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11941

Maintenance of normal levels of CP110 is essential to prevent over-duplication of centrosomes and genome instability; here, a deubiquitinating enzyme, USP33, is shown to stabilize CP110. USP33 enzyme supports centrosome duplication Centrosomes function as microtubule-organizing centres in cells and coordinate spindle pole formation during mitosis. Centrosome duplication is critical for cell division, and genome instability can result if duplication is not restricted to a single round per cell cycle. This process is controlled by the CP110 protein, and maintenance of normal CP110 levels is essential to prevent over-duplication of centrosomes. This study identifies USP33 (ubiquitin specific protease 33) as a centrosomal deubiquitinating enzyme that acts to stabilize CP110 at centrioles. USP33 positively regulates centrosome duplication by regulating CP110 abundance. These findings raise the possibility that deubiquitinating enzymes like USP33 might be therapeutic targets in cancers associated with centrosome amplification and genomic instability. 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, as 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 1 , 2 . CP110 levels are tightly controlled, partly through ubiquitination by the ubiquitin ligase complex SCF cyclin F during G2 and M phases of the cell cycle 3 . Here, using human cells, we report a new mechanism for the regulation of centrosome duplication that requires USP33, a deubiquitinating enzyme that is able to regulate CP110 levels. USP33 interacts with CP110 and localizes to centrioles primarily in S and G2/M phases, the periods during which centrioles duplicate and elongate. USP33 potently and specifically deubiquitinates CP110, but not other cyclin-F substrates. USP33 activity antagonizes SCF cyclin F -mediated ubiquitination and promotes the generation of supernumerary centriolar foci, whereas ablation of USP33 destabilizes CP110 and thereby inhibits centrosome amplification and mitotic defects. To our knowledge, we have identified the first centriolar deubiquitinating enzyme whose expression regulates centrosome homeostasis by countering cyclin-F-mediated destruction of a key substrate. Our results point towards potential therapeutic strategies for inhibiting tumorigenesis associated with centrosome amplification.