The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase

Autor: C. Johannes Gloeckner, Jeroen van Reeuwijk, Emine Bolat, Karsten Boldt, Susanne Roosing, Stef J.F. Letteboer, Ronald Roepman, Karlien L.M. Coene, Theo A. Peters, Dorus A. Mans, Marius Ueffing, Frans P.M. Cremers
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Genetics and epigenetic pathways of disease [NCMLS 6]
Protein family
Leber Congenital Amaurosis
Protein Serine-Threonine Kinases
Biology
Ciliopathies
Retina
Cell Line
Genomic disorders and inherited multi-system disorders [IGMD 3]
03 medical and health sciences
0302 clinical medicine
Cerebellar Diseases
Cerebellum
Genetics
Ciliary rootlet
medicine
Animals
Humans
NIMA-Related Kinases
Abnormalities
Multiple
Cilia
Eye Abnormalities
Rats
Wistar
Molecular Biology
Genetics (clinical)
Adaptor Proteins
Signal Transducing
030304 developmental biology
Serine/threonine-specific protein kinase
0303 health sciences
Cilium
Proteins
General Medicine
Kidney Diseases
Cystic
medicine.disease
Cilium assembly
Rats
Cytoskeletal Proteins
Ciliopathy
nima-related kinase
polycystic kidney-disease
regulator (rpgr)-interacting protein
leber congenital amaurosis
joubert-syndrome
retinal degeneration
statistical-model
ciliary rootlet
murine models
family kinase
RPGRIP1L
Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6]
Functional Neurogenomics [DCN 2]
030217 neurology & neurosurgery
Protein Binding
Zdroj: Hum. Mol. Genet. 20, 3592-3605 (2011)
Human Molecular Genetics; Vol 20
Human Molecular Genetics, 20, 3592-605
Human Molecular Genetics, 20, 18, pp. 3592-605
ISSN: 0964-6906
Popis: Contains fulltext : 97420.pdf (Publisher’s version ) (Closed access) Recent studies have established ciliary dysfunction as the underlying cause of a broad range of multi-organ phenotypes, known as 'ciliopathies'. Ciliopathy-associated proteins have a common site of action in the cilium, however, their overall importance for ciliary function differs, as implied by the extreme variability in ciliopathy phenotypes. The aim of this study was to gain more insight in the function of two ciliopathy-associated protein homologs, RPGR interacting protein 1 (RPGRIP1) and RPGRIP1-like protein (RPGRIP1L). Mutations in RPGRIP1 lead to the eye-restricted disease Leber congenital amaurosis, while mutations in RPGRIP1L are causative for Joubert and Meckel syndrome, which affect multiple organs and are at the severe end of the ciliopathy spectrum. Using tandem affinity purification in combination with mass spectrometry, we identified Nek4 serine/threonine kinase as a prominent component of both the RPGRIP1- as well as the RPGRIP1L-associated protein complex. In ciliated cells, this kinase localized to basal bodies, while in ciliated organs, the kinase was predominantly detected at the ciliary rootlet. Down-regulation of NEK4 in ciliated cells led to a significant decrease in cilium assembly, pointing to a role for Nek4 in cilium dynamics. We now hypothesize that RPGRIP1 and RPGRIP1L function as cilium-specific scaffolds that recruit a Nek4 signaling network which regulates cilium stability. Our data are in line with previously established roles in the cilium of other members of the Nek protein family and define NEK4 as a ciliopathy candidate gene.
Databáze: OpenAIRE
Externí odkaz: