Myosin VI regulates ciliogenesis by promoting the turnover of the centrosomal/satellite protein OFD1

Abstract

The actin motor protein myosin VI is a multivalent protein with diverse functions. Here, we identified and characterised a myosin VI ubiquitous interactor, the oral‐facial‐digital syndrome 1 (OFD1) protein, whose mutations cause malformations of the face, oral cavity, digits and polycystic kidney disease. We found that myosin VI regulates the localisation of OFD1 at the centrioles and, as a consequence, the recruitment of the distal appendage protein Cep164. Myosin VI depletion in non‐tumoural cell lines causes an aberrant localisation of OFD1 along the centriolar walls, which is due to a reduction in the OFD1 mobile fraction. Finally, loss of myosin VI triggers a severe defect in ciliogenesis that could be, at least partially, ascribed to an impairment in the autophagic removal of OFD1 from satellites. Altogether, our results highlight an unprecedent layer of regulation of OFD1 and a pivotal role of myosin VI in coordinating the formation of the distal appendages and primary cilium with important implications for the genetic disorders known as ciliopathies.

TTBK2 controls cilium stability by regulating distinct modules of centrosomal proteins

“…In addition to its role in the budding of ectosomes from the tips of cilia ( Nager et al. , 2017 ), myosin VI is also linked to ciliogenesis through regulation of centriolar satellites ( Magistrati et al. , 2021 ).…”

TTBK2 controls cilium stability through actin and the centrosomal compartment

“…4B ). In addition to its role in the budding of ectosomes from the tips of cilia (22), Myosin VI is also linked to ciliogenesis through regulation of centriolar satellites (29). We previously undertook biotin proximity labeling (BioID) with TTBK2 to identify proteins potentially in the TTBK2 ciliogenesis pathway (15).…”

“…Consistent with TIP temporarily attenuating cilia loss resulting from TTBK2 deletion, Myosin VI levels increased at the centrioles in Tmx-treated Ttbk2 cmut cells. In addition to its role in trafficking proteins along actin filaments, Myosin VI has also been reported to regulate the centriolar satellite composition (29). Recent evidence also suggests that the centriolar satellite scaffold PCM1 is also involved in cilia maintenance (42).…”

A planar-polarized MYO6-DOCK7-RAC1 axis promotes tissue fluidification in mammary epithelia

“…Indeed, our previous studies [31] and current bioinformatic analyses (Figure 7A) indicate that the myosin VI short isoform is selectively overexpressed in basal-like breast cancers. While the direct inhibition of myosin VI may have unwanted deleterious effects in normal tissues [58], the interaction surface with DOCK7 represents a promising target to explore in future drug discovery studies. (F) Quantification of cryptic lamellipodia protrusion persistence, performed as in Figure 2F for the indicated cell lines.…”