Direct binding of CEP85 to STIL ensures robust PLK4 activation and efficient centriole assembly

Liu, Yi; Gupta, Gagan D.; Barnabas, Deepak D.; Agircan, Fikret G.; Mehmood, Shahid; Wu, Di; Coyaud, Étienne; Johnson, Christopher M.; McLaughlin, Stephen H.; Andreeva, Antonina; Freund, Stefan; Robinson, Carol V.; Cheung, Sally W.T.; Raught, Brian; Pelletier, Laurence; Breugel, M. van

doi:10.1038/s41467-018-04122-x

Cited by 34 publications

(35 citation statements)

References 60 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although our model is formulated for mammalian cells, the principles of PLK4 symmetry breaking outlined above are likely to be conserved also in other organisms. Further concerted experimental and theoretical efforts will be required to increase the biological realism and predictive power of the model by the refinement of molecular mechanisms and incorporation of additional molecular players, such as CEP85, which was recently implicated in PLK4 activation ( Liu et al., 2018 ).…”

Section: Resultsmentioning

confidence: 99%

Autoamplification and Competition Drive Symmetry Breaking: Initiation of Centriole Duplication by the PLK4-STIL Network

2018

View full text Add to dashboard Cite

SummaryCentrioles, the cores of centrosomes and cilia, duplicate every cell cycle to ensure their faithful inheritance. How only a single procentriole is produced on each mother centriole remains enigmatic. We propose the first mechanistic biophysical model for procentriole initiation which posits that interactions between kinase PLK4 and its activator-substrate STIL are central for procentriole initiation. The model recapitulates the transition from a uniform “ring” of PLK4 surrounding the mother centriole to a single PLK4 “spot” that initiates procentriole assembly. This symmetry breaking requires autocatalytic activation of PLK4 and enhanced centriolar anchoring of PLK4 by phosphorylated STIL. We find that in situ degradation of active PLK4 cannot break symmetry. The model predicts that competition between transient PLK4 activity maxima for PLK4-STIL complexes destabilizes the PLK4 ring and produces instead a single PLK4 spot. Weakening of competition by overexpression of PLK4 and STIL causes progressive addition of supernumerary procentrioles, as observed experimentally.

show abstract

Section: Resultsmentioning

confidence: 99%

Autoamplification and Competition Drive Symmetry Breaking: Initiation of Centriole Duplication by the PLK4-STIL Network

2018

View full text Add to dashboard Cite

show abstract

“…Third, both satellites and a subgroup of P‐body proteins have been shown to move along MTs (Dammermann & Merdes, ; Aizer et al , ). Finally, a recent BioID‐based study on RNA bodies identified the centrosomal protein CEP85, a regulator of centriole duplication and PLK4 activity (Liu et al , ), as a high‐confidence prey for multiple P‐body baits. These observations suggest that satellites and centrosomes may play a yet undescribed role related to RNA processing and decay.…”

Section: Discussionmentioning

confidence: 99%

Spatial and proteomic profiling reveals centrosome‐independent features of centriolar satellites

et al. 2019

Self Cite

View full text Add to dashboard Cite

Centriolar satellites are small electron‐dense granules that cluster in the vicinity of centrosomes. Satellites have been implicated in multiple critical cellular functions including centriole duplication, centrosome maturation, and ciliogenesis, but their precise composition and assembly properties have remained poorly explored. Here, we perform in vivo proximity‐dependent biotin identification (Bio ID ) on 22 human satellite proteins, to identify 2,113 high‐confidence interactions among 660 unique polypeptides. Mining this network, we validate six additional satellite components. Analysis of the satellite interactome, combined with subdiffraction imaging, reveals the existence of multiple unique microscopically resolvable satellite populations that display distinct protein interaction profiles. We further show that loss of satellites in PCM 1‐depleted cells results in a dramatic change in the satellite interaction landscape. Finally, we demonstrate that satellite composition is largely unaffected by centriole depletion or disruption of microtubules, indicating that satellite assembly is centrosome‐independent. Together, our work offers the first systematic spatial and proteomic profiling of human centriolar satellites and paves the way for future studies aimed at better understanding the biogenesis and function(s) of these enigmatic structures.

show abstract

“…While our model is formulated for mammalian cells, the principles of PLK4 symmetry breaking outlined above are likely to be conserved also in other organisms. Further concerted experimental and theoretical efforts will be required to increase the biological realism and predictive power of the model by the refinement of molecular mechanisms and incorporation of additional molecular players, such as CEP85, which was recently implicated in PLK4 activation (Liu et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Autoamplification and competition drive symmetry breaking: Initiation of centriole duplication by the PLK4-STIL network

Leda

Holland

Goryachev

2018

Preprint

View full text Add to dashboard Cite

Symmetry breaking, a central principle of physics, has been hailed as the driver of selforganization in biological systems in general and biogenesis of cellular organelles in particular, but the molecular mechanisms of symmetry breaking only begin to become understood. Centrioles, the structural cores of centrosomes and cilia, must duplicate every cell cycle to ensure their faithful inheritance through cellular divisions. Work in model organisms identified conserved proteins required for centriole duplication and found that altering their abundance affects centriole number. However, the biophysical principles that ensure that, under physiological conditions, only a single procentriole is produced on each mother centriole remain enigmatic. Here we propose a mechanistic biophysical model for the initiation of procentriole formation in mammalian cells. We posit that interactions between the master regulatory kinase PLK4 and its activator-substrate STIL form the basis of the procentriole initiation network. The model faithfully recapitulates the experimentally observed transition from PLK4 uniformly distributed around the mother centriole, the "ring", to a unique PLK4 focus, the "spot", that triggers the assembly of a new procentriole. This symmetry breaking requires a dual positive feedback based on autocatalytic activation of PLK4 and enhanced centriolar anchoring of PLK4-STIL complexes by phosphorylated STIL. We find that, contrary to previous proposals, in situ degradation of active PLK4 is insufficient to break symmetry. Instead, the model predicts that competition between transient PLK4 activity maxima for PLK4-STIL complexes explains both the instability of the PLK4 ring and formation of the unique PLK4 spot. In the model, strong competition at physiologically normal parameters robustly produces a single procentriole, while increasing overexpression of PLK4 and STIL weakens the competition and causes progressive addition of procentrioles in agreement with experimental observations.

show abstract

Direct binding of CEP85 to STIL ensures robust PLK4 activation and efficient centriole assembly

Cited by 34 publications

References 60 publications

Autoamplification and Competition Drive Symmetry Breaking: Initiation of Centriole Duplication by the PLK4-STIL Network

Autoamplification and Competition Drive Symmetry Breaking: Initiation of Centriole Duplication by the PLK4-STIL Network

Spatial and proteomic profiling reveals centrosome‐independent features of centriolar satellites

Autoamplification and competition drive symmetry breaking: Initiation of centriole duplication by the PLK4-STIL network

Contact Info

Product

Resources

About