A ciliopathy complex builds distal appendages to initiate ciliogenesis

Abstract

Cells inherit two centrioles, the older of which is uniquely capable of generating a cilium. Using proteomics and superresolved imaging, we identify a module that we term DISCO (distal centriole complex). The DISCO components CEP90, MNR, and OFD1 underlie human ciliopathies. This complex localizes to both distal centrioles and centriolar satellites, proteinaceous granules surrounding centrioles. Cells and mice lacking CEP90 or MNR do not generate cilia, fail to assemble distal appendages, and do not transduce Hedgehog signals. Disrupting the satellite pools does not affect distal appendage assembly, indicating that it is the centriolar populations of MNR and CEP90 that are critical for ciliogenesis. CEP90 recruits the most proximal known distal appendage component, CEP83, to root distal appendage formation, an early step in ciliogenesis. In addition, MNR, but not CEP90, restricts centriolar length by recruiting OFD1. We conclude that DISCO acts at the distal centriole to support ciliogenesis by restraining centriole length and assembling distal appendages, defects in which cause human ciliopathies.

The Role of Centrosome Distal Appendage Proteins (DAPs) in Nephronophthisis and Ciliogenesis

“…The complex consists of three proteins, MNR, OFD1, and CEP90. MNR forms the innermost ring at the distal centriole and recruits OFD1, together with CEP90 [42]. CEP90 is a key component of the centriolar satellites and of the distal end of centrioles.…”

“…CEP90 is a key component of the centriolar satellites and of the distal end of centrioles. CEP90 regulates mother centriole function and recruits CEP83 to initiate distal appendage assembly at the mother centriole [42].…”

“…Consequently, depletion of CEP90 leads to mitotic arrest, misaligned chromosomes, spindle pole fragmentation, and centriole duplication defects [129,130]. Moreover, cells lacking CEP90 fail to remove CP110 and to recruit the DAP proteins CEP83, FBF1, SCLT1, and CEP164 [42].…”

“…Mice carrying a homozygous deletion of seven exons in Cep90 display cardiac looping defects, leading to early embryonic lethality. Further studies indicate that embryos and MEFs lacking Cep90 fail to assemble distal appendage-like structures, resulting in defective cilia assembly and disrupted Hedgehog signaling [42]. Interestingly, mutations in genes encoding for the other two components of the distal centriole complex, MNR/KIAA0753 (OMIM 617112), and OFD1 cause JBTS (MIM 300804) or orofaciodigital syndrome (MIM 311200) [42].…”

DISCO is key to successful centriole maturation

“…However, the precise mechanism by which DAs are assembled onto centrioles remains elusive. In this issue, Kumar et al focused their attention on CEP90, a poorly characterized protein whose mutations have been implicated in several ciliopathies ( 4 ). CEP90 is a component of centriolar satellites, which are proteinaceous granules located at the periphery of the centrosome ( 5 , 6 ).…”