Dataset Information

CEP19-RABL2 GTPase complex in ciliary transport

ABSTRACT: The mechanisms of how highly conserved intraflagellar transport (IFT) protein complexes direct ciliary entry remain unknown. Exploring human ciliopathy genes, including monogenic obesity syndrome genes, has been a rich source of critical ciliary mechanisms. Using AP-MS purification of interactors of the CEP19 monogenic obesity gene, we identify factors and the first known mechanism for triggering ciliary entry of IFT complexes. CEP19 binds the CEP350 and FOP centriolar components and the highly conserved RABL2 GTPase. We discovered that the CEP19-RABL2 complex is first recruited by the centriolar CEP350/FOP complex, concurrently activates nucleotide exchange to capture and release intraflagellar transport B holocomplexes from a large centriolar pool to intraflagellar transport. The CEP19 network of interacting proteins regulates ciliary entry and ciliation, providing a new example of ciliary mechanisms deficient in monogenic obesity syndromes.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Retinal Pigment Epithelial Cell, Retinal Pigment Epithelium Cell

SUBMITTER: Janos Demeter

LAB HEAD: Peter K. Jackson

PROVIDER: PXD006757 | Pride | 2017-06-21

REPOSITORIES: pride

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Dataset's files

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			Action	DRS
	160115_Jackson_NMooney_4822_Rabl2B_01.raw	Raw
	160115_Jackson_NMooney_4822_Rabl2B_01.raw_20160119_Byonic.mgf	Mgf
	160115_Jackson_NMooney_4822_Rabl2B_01.raw_20160119_Byonic.mzid.gz	Mzid
	160115_Jackson_NMooney_4822_Rabl2B_01.raw_20160119_Byonic.pride.mgf.gz	Mgf
	160115_Jackson_NMooney_4822_Rabl2B_01.raw_20160119_Byonic.pride.mztab.gz	Mztab

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Publications

The CEP19-RABL2 GTPase Complex Binds IFT-B to Initiate Intraflagellar Transport at the Ciliary Base.

Kanie Tomoharu T Abbott Keene Louis KL Mooney Nancie Ann NA Plowey Edward Douglas ED Demeter Janos J Jackson Peter Kent PK

Developmental cell 20170615 1

Highly conserved intraflagellar transport (IFT) protein complexes direct both the assembly of primary cilia and the trafficking of signaling molecules. IFT complexes initially accumulate at the base of the cilium and periodically enter the cilium, suggesting an as-yet-unidentified mechanism that triggers ciliary entry of IFT complexes. Using affinity-purification and mass spectrometry of interactors of the centrosomal and ciliopathy protein, CEP19, we identify CEP350, FOP, and the RABL2B GTPase ...[more]

PMID: 28625565

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Project description:Study Smoking and COPD are associated with decreased mucociliary clearance and healthy smokers have shorter cilia in the large airway than nonsmokers. Intraflagellar transport (IFT) is the process by which cilia are produced and maintained. We assessed expression of IFT-related genes in smokers and nonsmokers and evaluated cilia length in the large and small airway of nonsmokers, healthy smokers, and smokers with COPD. Methods Airway epithelium was obtained via bronchoscopic brushing. Affymetrix microarrays were used to evaluate IFT gene expression in 2 independent data sets from large and small airway. Cilia length was assessed by measuring 100 cilia (10 cilia on each of 10 cells) per subject. Results All 40 IFT genes were expressed in the human large and small airway epithelium. In the large airway, 10 IFT genes were down-regulated and 1 up-regulated in smokers. In the small airway, 11 genes were down-regulated and 3 up-regulated in smokers. A set of 8 IFT genes was down-regulated in both data sets. In the large and small airway epithelium, cilia were significantly shorter in healthy smokers than nonsmokers, and significantly shorter in COPD smokers than in both healthy smokers and nonsmokers. Answer to the Question These results support the concept that loss of cilia length contributes to defective mucociliary clearance in COPD, and that smoking-induced changes in expression of IFT genes may be one mechanism of abnormally short cilia in smokers. Strategies to normalize cilia length may be an important avenue for novel COPD therapies. Gene expression was assessed for 40 intraflagellar transport related genes in the LAE of nonsmokers (n=21) and healthy smokers (n=31) and the SAE of an independent group of nonsmokers (n=28) and healthy smokers (n=69). Cilia length was assessed in a total of 228 airway epithelium samples, including 120 LAE samples and 108 SAE samples; a subset of the 228 samples is represented among the 149 samples in this Series.