Abstract
Centriole biogenesis and maintenance are crucial for cells to generate cilia and assemble centrosomes that function as microtubule organizing centers (MTOCs). Centriole biogenesis and MTOC function both require the microtubule nucleator γ-tubulin ring complex (γTuRC). It is widely accepted that γTuRC nucleates microtubules from the pericentriolar material that is associated with the proximal part of centrioles. However, γTuRC also localizes more distally and in the centriole lumen, but the significance of these findings is unclear. Here we identify spatially and functionally distinct subpopulations of centrosomal γTuRC. Luminal localization is mediated by augmin, which is linked to the centriole inner scaffold through POC5. Disruption of luminal localization impairs centriole integrity and interferes with cilium assembly. Defective ciliogenesis is also observed in γTuRC mutant fibroblasts from a patient suffering from microcephaly with chorioretinopathy. These results identify a non-canonical role of augmin-γTuRC in the centriole lumen that is linked to human disease.
Highlights
Centriole biogenesis and maintenance are crucial for cells to generate cilia and assemble centrosomes that function as microtubule organizing centers (MTOCs)
The cone-shaped γ-tubulin ring complex (γTuRC) is assembled from γ-tubulin complex proteins (GCPs) 2–6, MZT1, MZT2, an actin-like protein, and multiple γ-tubulin molecules at its open face that have been proposed to function as template for α-β-tubulin assembly[17,18,19,20,21]
To identify potential centrosomal subpopulations of γTuRC and elucidate whether these may have distinct functions, we analyzed the centrosomal localization of the γTuRC targeting factor NEDD15,22 and of the core subunits γ-tubulin and GCP4 by expansion microscopy (ExM)36. γTuRC subunits localized on the outer surface of both mother and daughter centrioles, visualized with anti-acetylated αtubulin antibodies, in some cases displaying enrichment in the proximal part of mother centrioles
Summary
Centriole biogenesis and maintenance are crucial for cells to generate cilia and assemble centrosomes that function as microtubule organizing centers (MTOCs). Defective ciliogenesis is observed in γTuRC mutant fibroblasts from a patient suffering from microcephaly with chorioretinopathy These results identify a non-canonical role of augmin-γTuRC in the centriole lumen that is linked to human disease. 1234567890():,; Centrioles, which are at the core of the centrosome and template the formation of cilia, are formed by nine sets of microtubules that are arranged in a circular fashion so that they form the wall of a cylinder. Wall microtubules of mature centrioles are organized as triplets and doublets in the proximal and distal cylinder, respectively. The mother centriole transforms into a basal body and templates formation of the axoneme, a microtubule-based structure that is at the core of cilia. Axoneme microtubules are believed to not require nucleation but originate from elongation of the doublet microtubules in the distal basal body wall[35]. Luminal augmin-γTuRC does not nucleate microtubules but contributes to centriole integrity, maintaining the ability of centrioles to template cilium formation
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