Moonlighting of mitotic regulators in cilium disassembly

Abstract

Correct timing of cellular processes is essential during embryological development and to maintain the balance between healthy proliferation and tumour formation. Assembly and disassembly of the primary cilium, the cell's sensory signalling organelle, are linked to cell cycle timing in the same manner as spindle pole assembly and chromosome segregation. Mitotic processes, ciliary assembly, and ciliary disassembly depend on the centrioles as microtubule-organizing centres (MTOC) to regulate polymerizing and depolymerizing microtubules. Subsequently, other functional protein modules are gathered to potentiate specific protein-protein interactions. In this review, we show that a significant subset of key mitotic regulator proteins is moonlighting at the cilium, among which PLK1, AURKA, CDC20, and their regulators. Although ciliary assembly defects are linked to a variety of ciliopathies, ciliary disassembly defects are more often linked to brain development and tumour formation. Acquiring a better understanding of the overlap in regulators of ciliary disassembly and mitosis is essential in finding therapeutic targets for the different diseases and types of tumours associated with these regulators.

Keywords: Cell cycle regulators; Centrioles; Cilia; Cilium resorption; Tumour development; WNT.

Fig. 1

Cilia and ciliation cycle. a Graphic representation of the centrioles. During mitosis (M phase) the centrioles form the spindle poles to separate the nuclear material. In quiescence (G0 phase) the centrioles (red) are positioned at the base of the cilium (green). b The cilia assemble every cell cycle in G0/G1 phase and disassemble during S/G2 phase, during which the centrioles are positioned at the ciliary base. After detachment from the plasma membrane, the linker between the mother and daughter centriole dissolves, allowing the two centrioles to move towards the nucleus to form the spindle poles. Each mother centriole forms a new daughter centriole during the next cycle. c The centrosomes, displaying two structurally different centrioles surrounded by the pericentriolar material (PCM), act as the main MTOC both during spindle pole formation and ciliogenesis. Nonetheless, an MTOC can also arise without a centrosome [174]. The spindle pole and basal body refer to the centrosome as an MTOC with the pericentriolar material, but either contain proteins specific to the cell cycle, or ciliogenesis. The centrosomes gather different complexes for these specific functions, enriching the PCM for different sets of proteins, and making it more likely for interacting proteins to bind at the right phase of the cell cycle. d Schematic representation of the cilia and the ciliary regions that can be distinguished

Fig. 2

Ciliary disassembly mechanism. a A schematic representation of ciliary resorption versus ciliary excision. b The core axis of ciliary disassembly is regulated through the NEDD9/AURKA/HDAC6 pathway that drives ciliary resorption. This axis can be stimulated by the mitochondria, extracellular WNT signalling and cell cycle regulators. The criteria for a protein to be considered a ciliary resorption protein, and to be included in this schematic overview, the protein has to influence ciliary length during disassembly, but is not involved in ciliary excision or budding. All of these proteins with a confirmed role in ciliary resorption are shown in blue. In addition to these, proteins shown in grey and with dotted lines indicate known interactors of these resorption proteins, but which have not yet been investigated in the context of ciliary resorption specifically. PLK1 both stimulates and inhibits ciliary resorption by phosphorylation of a wide variety of targets. The APC/C stimulates ciliary resorption when activated by CDC20. For CENPJ, the exact role in ciliary resorption remains elusive

Fig. 3

Conservation between the cilia, kinetochores and spindle poles. a Schematic representation of the kinetochore, and the key proteins present in each part of this structure. Individual proteins are indicated as circles (blue), protein complexes as squares (green). The MTs are docked onto the outer kinetochore. The corona contains many different proteins and protein complexes (inset), which either affect MT and dynein organization or cell cycle regulation. The MTs are bundled and crosslinked to withstand the high mechanical forces between the kinetochores and spindle poles prior to and upon segregation of the sister chromatids. b Many proteins and protein complexes are conserved between the cilia, kinetochores and spindle poles. Proteins that have been confirmed to play a role in ciliary resorption are marked (bold). The proteins are sorted per module and their organization in the two structures seems to be dependent on the MT organization, from minus at the bottom to plus at the top