title: Regulation of autophosphorylation controls PLK4 self-destruction and centriole number.
abstract: Polo-like kinase 4 (PLK4) is a major player in centriole biogenesis: in its absence centrioles fail to form, while in excess leads to centriole amplification. The SCF-Slimb/βTrCP-E3 ubiquitin ligase controls PLK4 levels through recognition of a conserved phosphodegron. SCF-Slimb/βTrCP substrate binding and targeting for degradation is normally regulated by phosphorylation cascades, controlling complex processes, such as circadian clocks and morphogenesis. Here, we show that PLK4 is a suicide kinase, autophosphorylating in residues that are critical for SCF-Slimb/βTrCP binding. We demonstrate a multisite trans-autophosphorylation mechanism, likely to ensure that both a threshold of PLK4 concentration is attained and a sequence of events is observed before PLK4 can autodestruct. First, we show that PLK4 trans-autophosphorylates other PLK4 molecules on both Ser293 and Thr297 within the degron and that these residues contribute differently for PLK4 degradation, the first being critical and the second maximizing auto-destruction. Second, PLK4 trans-autophosphorylates a phospho-cluster outside the degron, which regulates Thr297 phosphorylation, PLK4 degradation, and centriole number. Finally, we show the importance of PLK4-Slimb/βTrCP regulation as it operates in both soma and germline. As βTrCP, PLK4, and centriole number are deregulated in several cancers, our work provides novel links between centriole number control and tumorigenesis.
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal. Electronic address: ananasferreira@gmail.com.
authors.forename: Inês
authors.initials: I
authors.lastname: Cunha-Ferreira
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Bento
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Pimenta-Marques
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
authors.forename: Swadhin Chandra
authors.initials: SC
authors.lastname: Jana
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
authors.forename: Mariana
authors.initials: M
authors.lastname: Lince-Faria
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Duarte
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Borrego-Pinto
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
authors.forename: Samuel
authors.initials: S
authors.lastname: Gilberto
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
authors.forename: Tiago
authors.initials: T
authors.lastname: Amado
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
authors.forename: Daniela
authors.initials: D
authors.lastname: Brito
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Rodrigues-Martins
authors.affiliation: Institute of Biochemistry and Biophysics, PAS, Pawinskiego 5a, 02-106, Warszawa, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Debski
authors.affiliation: Cancer Research UK Cell Cycle Genetics Group, Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
authors.forename: Nikola
authors.initials: N
authors.lastname: Dzhindzhev
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal. Electronic address: mdias@igc.gulbenkian.pt.
authors.forename: Mónica
authors.initials: M
authors.lastname: Bettencourt-Dias
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002502:Centrioles / Q000378:metabolism*; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; C110233:slmb protein, Drosophila; D013912:Threonine; D012694:Serine; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; C522064:Sak protein, Drosophila