PHD1 links cell-cycle progression to oxygen sensing through hydroxylation of the centrosomal protein Cep192.
PHD1 belongs to the family of prolyl-4-hydroxylases (PHDs) that is responsible for posttranslational modification of prolines on specific target proteins. Because PHD activity is sensitive to oxygen levels and certain byproducts of the tricarboxylic acid cycle, PHDs act as sensors of the cell's metabolic state. Here, we identify PHD1 as a critical molecular link between oxygen sensing and cell-cycle control. We show that PHD1 function is required for centrosome duplication and maturation through modification of the critical centrosome component Cep192. Importantly, PHD1 is also required for primary cilia formation. Cep192 is hydroxylated by PHD1 on proline residue 1717. This hydroxylation is required for binding of the E3 ubiquitin ligase SCF(Skp2), which ubiquitinates Cep192, targeting it for proteasomal degradation. By modulating Cep192 levels, PHD1 thereby affects the processes of centriole duplication and centrosome maturation and contributes to the regulation of cell-cycle progression.
Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Sandra C
SC
Moser
Dalila
D
Bensaddek
Brian
B
Ortmann
Jean-Francois
JF
Maure
Sharon
S
Mudie
J Julian
JJ
Blow
Angus I
AI
Lamond
Jason R
JR
Swedlow
Sonia
S
Rocha
D000595:Amino Acid Sequence; D002453:Cell Cycle / Q000187:drug effects*; D002502:Centrioles / Q000187:drug effects / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D008954:Models, Biological; D008969:Molecular Sequence Data; D010100:Oxygen / Q000494:pharmacology*; D011392:Proline / Q000378:metabolism; D011485:Protein Binding; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
C526596:Cep192 protein, human; D002868:Chromosomal Proteins, Non-Histone; D044786:S-Phase Kinase-Associated Proteins; D011392:Proline; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen