Nephronophthisis is the most common genetic cause of end-stage renal failure during childhood and adolescence. Genetic studies
have identified disease-causing mutations in at least 11 different genes (NPHP1–11), but the function of the corresponding nephrocystin proteins remains poorly understood. The two evolutionarily conserved
proteins nephrocystin-1 (NPHP1) and nephrocystin-4 (NPHP4) interact and localize to cilia in kidney, retina, and brain characterizing
nephronophthisis and associated pathologies as result of a ciliopathy. Here we show that NPHP4, but not truncating patient
mutations, negatively regulates tyrosine phosphorylation of NPHP1. NPHP4 counteracts Pyk2-mediated phosphorylation of three
defined tyrosine residues of NPHP1 thereby controlling binding of NPHP1 to the trans-Golgi sorting protein PACS-1. Knockdown
of NPHP4 resulted in an accumulation of NPHP1 in trans-Golgi vesicles of ciliated retinal epithelial cells. These data strongly
suggest that NPHP4 acts upstream of NPHP1 in a common pathway and support the concept of a role for nephrocystin proteins
in intracellular vesicular transport.
"In C. elegans, the NPHP1 homolog nph-1 is part of a protein complex that regulates basal body anchoring  and together with the NPHP4 homolog nph-4 modifies the structure of the microtubule-based ciliary axoneme . Recent data point to roles for NPHP1 and NPHP4 in signaling  and vesicular trafficking , . Very recently, Sang et al. described the composition of three distinct NPH protein complexes functioning at different cellular sites . "
[Show abstract][Hide abstract] ABSTRACT: Polo-like kinase (Plk1) plays a central role in regulating the cell cycle. Plk1-mediated phosphorylation is essential for centrosome maturation, and for numerous mitotic events. Although Plk1 localizes to multiple subcellular sites, a major site of action is the centrosomes, which supports mitotic functions in control of bipolar spindle formation. In G0 or G1 untransformed cells, the centriolar core of the centrosome differentiates into the basal body of the primary cilium. Primary cilia are antenna-like sensory organelles dynamically regulated during the cell cycle. Whether Plk1 has a role in ciliary biology has never been studied. Nephrocystin-1 (NPHP1) is a ciliary protein; loss of NPHP1 in humans causes nephronophthisis (NPH), an autosomal-recessive cystic kidney disease. We here demonstrate that Plk1 colocalizes with nephrocystin-1 to the transition zone of primary cilia in epithelial cells. Plk1 co-immunoprecipitates with NPHP1, suggesting it is part of the nephrocystin protein complex. We identified a candidate Plk1 phosphorylation motif (D/E-X-S/T-φ-X-D/E) in nephrocystin-1, and demonstrated in vitro that Plk1 phosphorylates the nephrocystin N-terminus, which includes the specific PLK1 phosphorylation motif. Further, induced disassembly of primary cilia rapidly evoked Plk1 kinase activity, while small molecule inhibition of Plk1 activity or RNAi-mediated downregulation of Plk1 limited the first and second phase of ciliary disassembly. These data identify Plk1 as a novel transition zone signaling protein, suggest a function of Plk1 in cilia dynamics, and link Plk1 to the pathogenesis of NPH and potentially other cystic kidney diseases.
PLoS ONE 06/2012; 7(6):e38838. DOI:10.1371/journal.pone.0038838 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Loss of cilia and ciliary protein causes various abnormalities (called ciliopathy), including situs inversus, renal cystic diseases, polydactyly and dysgenesis of the nervous system. Renal cystic diseases are the most frequently observed symptoms in ciliopathies. Cilia are microtubule-based organelles with the following regions: a ciliary tip, shaft, transitional zone and basal body/mother centriole. Joubert syndrome (JBTS), Meckel Gruber syndrome (MKS) and Nephronophthisis (NPHP) are overlapping syndromes. Recent studies show that JBST and MKS responsible gene products are localized in the transitional zone of the cilia, where they function as a diffusion barrier, and control protein sorting and ciliary membrane composition. Nephrocystins are gene products of NPHP responsible genes, and at least 11 genes have been identified. Although some nephrocystins interact with JBST and MKS proteins, proteomic analysis suggests that they do not form a single complex. Localization analysis reveals that nephrocystins can be divided into two groups. Group I nephrocystins are localized in the transitional zone, whereas group II nephrocystins are localized in the Inv compartment. Homologs of group I nephrocystins, but not group II nephrocystins, have been reported in C. reinhardtii and C. elegans. In this review, we summarize the structure of the ciliary base of C. reinhardtii, C. elegans and mammalian primary cilia, and discuss function of nephrocystins. We also propose a new classification of nephrocystins.
[Show abstract][Hide abstract] ABSTRACT: Nephronophthisis (NPH) comprises a group of autosomal recessive cystic kidney diseases and is the most frequent genetic cause of end-stage renal disease in children and adolescents. Causative mutations in more than a dozen genes have been identified that encode for the NPH protein family. Almost all of these proteins localize to primary cilia leading to the classification of NPH as a ciliopathy. The purpose of this review is to highlight the latest research on the molecular pathogenesis of the ciliopathy NPH.
Recent identification of novel disease causing genes and research on the localization and signaling function of nephrocystins have paved the way to a more detailed understanding of the molecular and cellular pathology of NPH and associated ciliopathies.
Here we discuss the most recently identified NPH related genes, the role of the NPH protein complex in ciliary biology and recently discovered functions of NPH proteins in cellular signaling.
Current opinion in nephrology and hypertension 03/2012; 21(3):272-8. DOI:10.1097/MNH.0b013e3283520f17 · 3.96 Impact Factor
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