Actin remodelling factors control ciliogenesis by regulating YAP/TAZ activity and vesicle trafficking

Abstract

Primary cilia exert a profound impact on cell signalling and cell cycle progression. Recently, actin cytoskeleton destabilization has been recognized as a dominant inducer of ciliogenesis, but the exact mechanisms regulating ciliogenesis remain poorly understood. Here we show that the actin cytoskeleton remodelling controls ciliogenesis by regulating transcriptional coactivator YAP/TAZ as well as ciliary vesicle trafficking. Cytoplasmic retention of YAP/TAZ correlates with active ciliogenesis either in spatially confined cells or in cells treated with an actin filament destabilizer. Moreover, knockdown of YAP/TAZ is sufficient to induce ciliogenesis, whereas YAP/TAZ hyperactivation suppresses serum starvation-mediated ciliogenesis. We also identify actin remodelling factors LIMK2 and TESK1 as key players in the ciliogenesis control network in which YAP/TAZ and directional vesicle trafficking are integral components. Our work provides new insights for understanding the link between actin dynamics and ciliogenesis.

YAP and TAZ: a nexus for Hippo signaling and beyond

“…The Hippo pathway both controls and is regulated by the primary cilia [94,153–155], a microtubule-based solitary sensory signaling organelle comprising a special part of the plasma membrane in most eukaryotic quiescent cells [156]. The primary cilia respond to mechanical signals [157] and dynamically localize and regulate a range of receptors mediated by YAP/TAZ, such as GPCRs, sonic hedgehog (shh), the TGFβ family, receptor tyrosine kinases, and Wnt receptors [7,10,14,17,22,23,158].…”

Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes

“…Unlike cytoD, eupatilin treatment did not induce ciliogenesis in the presence of serum ( Figure 1F) and did not alter the structure of the actin cytoskeleton (Supplemental Figure 3A). Moreover, Ki67 expression and YAP nuclear enrichment, which reflect cell proliferation and cilium disassembly gene expression (14), respectively, were only affected by cytoD treatment (Supplemental Figure 3, B-D). Cell proliferation assay validated that eupatilin exerts a lower inhibitory effect on cell proliferation when compared with cytoD (Supplemental Figure 3E).…”

STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis

“…13 Consistent with these observations, nucleating factors that promote actin polymerization repress primary cilium assembly and growth whereas actin severing enzymes promote ciliogenesis. [14][15][16][17] Actin depolymerization promotes ciliogenesis by stabilizing the pericentrosomal preciliary compartment, a vesiculotubular structure that contributes to ciliogenesis, 14,15,17 and by inhibiting transcription factors from the Hippo pathway, which induce the expression of cilium disassembly factors. 17 The small GTPase RhoA plays a key role in actin network regulation.…”

“…[14][15][16][17] Actin depolymerization promotes ciliogenesis by stabilizing the pericentrosomal preciliary compartment, a vesiculotubular structure that contributes to ciliogenesis, 14,15,17 and by inhibiting transcription factors from the Hippo pathway, which induce the expression of cilium disassembly factors. 17 The small GTPase RhoA plays a key role in actin network regulation. 18 It is required to promote actin stress fiber assembly and maintenance, through a signaling pathway that includes activation of Rho kinase and phosphorylation of myosin light chain 2 (MLC2).…”