Bimodal Binding of STIL to Plk4 Controls Proper Centriole Copy Number

Abstract

The number of centrioles is tightly controlled to ensure bipolar spindle assembly, which is a prerequisite to maintain genome integrity. However, our understanding of the fundamental principle that governs the formation of a single procentriole per parental centriole is incomplete. Here, we show that the local restriction of Plk4, a master regulator of the procentriole formation, is achieved by a bimodal interaction of STIL with Plk4. We demonstrate that the conserved short coiled-coil region of STIL binds to and protects Plk4 from protein degradation at the site of procentriole formation. On the other hand, the conserved C-terminal region of STIL named truncated in microcephaly (TIM) domain promotes autophosphorylation and degradation of adjacent Plk4 by the direct interaction. Thus, we propose that positive and negative regulation based on the bimodal binding of Plk4 and STIL ensures the formation of a single procentriole per parental centriole.

A free-running oscillator times and executes centriole biogenesis

“…Polo-like kinase 4 (Plk4) is the master regulator of centriole biogenesis, and it is initially recruited to a ring around the mother centriole, but this ring ultimately resolves into a single focus on the side of the mother, defining the site of daughter centriole assembly (Banterle and Gönczy, 2017;Fırat-Karalar and Stearns, 2014;Leda et al, 2018;Nigg and Holland, 2018;Ohta et al, 2018). Unexpectedly, we found that Plk4 not only determines the position of this site, but also helps to establish the inverse relationship between the rate and period of daughter centriole growth .…”

“…Recent studies have shown that Plk4 localizes to centrioles in a cyclical manner in both fly embryos and human cultured cells (Ohta et al, 2018), but the functional significance of this localisation pattern is unclear. Here, we demonstrate that Plk4 forms a cell-cycle autonomous oscillator at the base of the growing centriole that initiates and times centriole biogenesis in fly embryos.…”

14-3-3γ prevents centrosome duplication by inhibiting NPM1 function

“…In contrast, the expression of a phospho-mimetic mutant, T199D, leads to centrosome amplification (24). During Sphase, Polo-Like Kinase 4 (Plk4) recruitment at the site of procentriole biogenesis initiates centriole duplication (25,26). Overexpression of Plk4 results in centrosome amplification and its depletion results in a loss of centrioles (27,28).…”

“…Overexpression of Plk4 results in centrosome amplification and its depletion results in a loss of centrioles (27,28). During G2, procentrioles elongate and the mother centrioles mature and acquire distal and sub-distal appendages and the ability to nucleate PCM (5,21,26,28,29). Before entry into mitosis, CDK1 mediates the separation of centrosomes to the two poles, leading to the formation of a bipolar spindle (29)(30)(31)).…”

Cep57 and Cep57l1 cooperate to recruit the Cep63-Cep152 complex for centriole biogenesis

“…To initiate the centriole duplication in mammals, Plk4 is firstly recruited by the Cep192-containing ring around the proximal mother centrioles at the early G1 phase and subsequently translocated to the larger Cep152-containing ring when Cep152 is recruited to the mother centriole(Kim et al, 2013; Sonnen et al, 2013). At the Cep152-ring, Plk4 recruits and phosphorylates Stil/Sas-5 to load Sas-6 for the cartwheel formation (Arquint et al, 2015; Arquint et al, 2012; Cizmecioglu et al, 2010; Dzhindzhev et al, 2010; Moyer et al, 2015; Ohta et al, 2014; Ohta et al, 2018). Several proteins, including Cep135, Cpap, Cp110 and Cep120, contribute to build the centriolar MT wall and mediate centriole elongation(Azimzadeh and Marshall, 2010; Brito et al, 2012; Carvalho-Santos et al, 2012; Comartin et al, 2013; Hung et al, 2004; Kohlmaier et al, 2009; Loncarek and Bettencourt-Dias, 2018; Schmidt et al, 2009).…”