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The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery.

ABSTRACT: Cilia use microtubule-based intraflagellar transport (IFT) to organize intercellular signaling. Ciliopathies are a spectrum of human diseases resulting from defects in cilia structure or function. The mechanisms regulating the assembly of ciliary multiprotein complexes and the transport of these complexes to the base of cilia remain largely unknown. Combining proteomics, in vivo imaging and genetic analysis of proteins linked to planar cell polarity (Inturned, Fuzzy and Wdpcp), we identified and characterized a new genetic module, which we term CPLANE (ciliogenesis and planar polarity effector), and an extensive associated protein network. CPLANE proteins physically and functionally interact with the poorly understood ciliopathy-associated protein Jbts17 at basal bodies, where they act to recruit a specific subset of IFT-A proteins. In the absence of CPLANE, defective IFT-A particles enter the axoneme and IFT-B trafficking is severely perturbed. Accordingly, mutation of CPLANE genes elicits specific ciliopathy phenotypes in mouse models and is associated with ciliopathies in human patients.

SUBMITTER: Toriyama M

PROVIDER: S-EPMC4978421 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery.

Toriyama Michinori M Lee Chanjae C Taylor S Paige SP Duran Ivan I Cohn Daniel H DH Bruel Ange-Line AL Tabler Jacqueline M JM Drew Kevin K Kelly Marcus R MR Kim Sukyoung S Park Tae Joo TJ Braun Daniela A DA Pierquin Ghislaine G Biver Armand A Wagner Kerstin K Malfroot Anne A Panigrahi Inusha I Franco Brunella B Al-Lami Hadeel Adel HA Yeung Yvonne Y Choi Yeon Ja YJ Duffourd Yannis Y Faivre Laurence L Rivière Jean-Baptiste JB Chen Jiang J Liu Karen J KJ Marcotte Edward M EM Hildebrandt Friedhelm F Thauvin-Robinet Christel C Krakow Deborah D Jackson Peter K PK Wallingford John B JB

Nature genetics 20160509 6

Cilia use microtubule-based intraflagellar transport (IFT) to organize intercellular signaling. Ciliopathies are a spectrum of human diseases resulting from defects in cilia structure or function. The mechanisms regulating the assembly of ciliary multiprotein complexes and the transport of these complexes to the base of cilia remain largely unknown. Combining proteomics, in vivo imaging and genetic analysis of proteins linked to planar cell polarity (Inturned, Fuzzy and Wdpcp), we identified and ...[more]

PMID: 27158779

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Project description:Ciliopathies are inherited disorders caused by defective cilia. Mutations affecting motile cilia usually cause the chronic muco-obstructive sinopulmonary disease primary ciliary dyskinesia (PCD) and are associated with laterality defects, while a broad spectrum of early developmental as well as degenerative syndromes arise from mutations affecting signalling of primary (non-motile) cilia. Cilia assembly and functioning requires intraflagellar transport (IFT) of cargos assisted by IFT-B and IFT-A adaptor complexes. Within IFT-B, the N-termini of partner proteins IFT74 and IFT81 govern tubulin transport to build the ciliary microtubular cytoskeleton. We detected a homozygous 3-kb intragenic IFT74 deletion removing the exon 2 initiation codon and 40 N-terminal amino acids in two affected siblings. Both had clinical features of PCD with bronchiectasis, but no laterality defects. They also had retinal dysplasia and abnormal bone growth, with a narrowed thorax and short ribs, shortened long bones and digits, and abnormal skull shape. This resembles short-rib thoracic dysplasia, a skeletal ciliopathy previously linked to IFT defects in primary cilia, not motile cilia. Ciliated nasal epithelial cells collected from affected individuals had reduced numbers of shortened motile cilia with disarranged microtubules, some misorientation of the basal feet, and disrupted cilia structural and IFT protein distributions. No full-length IFT74 was expressed, only truncated forms that were consistent with N-terminal deletion and inframe translation from downstream initiation codons. In affinity purification mass spectrometry, exon 2-deleted IFT74 initiated from the nearest inframe downstream methionine 41 still interacts as part of the IFT-B complex, but only with reduced interaction levels and not with all its usual IFT-B partners. We propose that this is a hypomorphic mutation with some residual protein function retained, which gives rise to a primary skeletal ciliopathy combined with defective motile cilia and PCD.

Dataset Information

The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery.

Publications

The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery.

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