Abstract
Cilia play critical roles during embryonic development and adult homeostasis. Dysfunction of cilia leads to various human genetic diseases, including many caused by defects in transition zones (TZs), the "gates" of cilia. The evolutionarily conserved TZ component centrosomal protein 290 (CEP290) is the most frequently mutated human ciliopathy gene, but its roles in ciliogenesis are not completely understood. Here, we report that CEP290 plays an essential role in the initiation of TZ assembly in Drosophila. Mechanistically, the N-terminus of CEP290 directly recruits DAZ interacting zinc finger protein 1 (DZIP1), which then recruits Chibby (CBY) and Rab8 to promote early ciliary membrane formation. Complete deletion of CEP290 blocks ciliogenesis at the initiation stage of TZ assembly, which can be mimicked by DZIP1 deletion mutants. Remarkably, expression of the N-terminus of CEP290 alone restores the TZ localization of DZIP1 and subsequently ameliorates the defects in TZ assembly initiation in cep290 mutants. Our results link CEP290 to DZIP1-CBY/Rab8 module and uncover a previously uncharacterized important function of CEP290 in the coordination of early ciliary membrane formation and TZ assembly.
Highlights
Cilia are microtubule-based organelles that extend from the surface of most eukaryotic cells
We observed that the distribution of centrosomal protein 290 (CEP290)-N signal was significantly more restricted than the full-length CEP290 signal (Fig 1B), suggesting that CEP290-N is restricted toward the proximal part of the transition zone (TZ)
Ciliogenesis begins with the basal body (BB) docking, followed by the subsequent formation of the early ciliary shaft membrane and assembly of the TZ, which together form the ciliary bud
Summary
Cilia are microtubule-based organelles that extend from the surface of most eukaryotic cells. These protrusions are important for diverse cellular functions, including cell signaling, sensory perception, cell motility, and extracellular fluid movement [1,2,3,4]. Almost every cell has at least 1 cilium. Due to the ubiquitous distribution and important functions of cilia, ciliary dysfunction results in a wide variety of human genetic disorders, collectively termed ciliopathies [5,6]. Cilia arise from the distal ends of basal bodies (BBs) that are derived from mother centrioles. Depending on the cell type, cilia form through 1 of 2 pathways: the intracellular pathway
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