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

TL;DR

This paper presents a biophysical model explaining how symmetry breaking in centriole duplication is driven by PLK4-STIL network dynamics, leading to the formation of a single procentriole through autocatalytic feedback and competition mechanisms.

Contribution

It introduces a novel mechanistic model that explains the initiation of procentriole formation and the role of competition in symmetry breaking, aligning with experimental data.

Findings

Symmetry breaking involves autocatalytic activation of PLK4 and phosphorylated STIL.

Competition between PLK4 activity maxima explains the formation of a single procentriole.

Overexpression of PLK4 and STIL leads to multiple procentrioles, consistent with experiments.

Abstract

Symmetry breaking, a central principle of physics, has been hailed as the driver of self-organization 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. 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.