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The nucleoside-diphosphate kinase NME3 associates with nephronophthisis proteins and is required for ciliary function during renal development.

ABSTRACT: Nephronophthisis (NPH) is an autosomal recessive renal disease leading to kidney failure in children and young adults. The protein products of the corresponding genes (NPHPs) are localized in primary cilia or their appendages. Only about 70% of affected individuals have a mutation in one of 100 renal ciliopathy genes, and no unifying pathogenic mechanism has been identified. Recently, some NPHPs, including NIMA-related kinase 8 (NEK8) and centrosomal protein 164 (CEP164), have been found to act in the DNA-damage response pathway and to contribute to genome stability. Here, we show that NME/NM23 nucleoside-diphosphate kinase 3 (NME3) that has recently been found to facilitate DNA-repair mechanisms binds to several NPHPs, including NEK8, CEP164, and ankyrin repeat and sterile α motif domain-containing 6 (ANKS6). Depletion of nme3 in zebrafish and Xenopus resulted in typical ciliopathy-associated phenotypes, such as renal malformations and left-right asymmetry defects. We further found that endogenous NME3 localizes to the basal body and that it associates also with centrosomal proteins, such as NEK6, which regulates cell cycle arrest after DNA damage. The ciliopathy-typical manifestations of NME3 depletion in two vertebrate in vivo models, the biochemical association of NME3 with validated NPHPs, and its localization to the basal body reveal a role for NME3 in ciliary function. We conclude that mutations in the NME3 gene may aggravate the ciliopathy phenotypes observed in humans.

SUBMITTER: Hoff S

PROVIDER: S-EPMC6166740 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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The nucleoside-diphosphate kinase NME3 associates with nephronophthisis proteins and is required for ciliary function during renal development.

Hoff Sylvia S Epting Daniel D Falk Nathalie N Schroda Sophie S Braun Daniela A DA Halbritter Jan J Hildebrandt Friedhelm F Kramer-Zucker Albrecht A Bergmann Carsten C Walz Gerd G Lienkamp Soeren S SS

The Journal of biological chemistry 20180815 39

Nephronophthisis (NPH) is an autosomal recessive renal disease leading to kidney failure in children and young adults. The protein products of the corresponding genes (NPHPs) are localized in primary cilia or their appendages. Only about 70% of affected individuals have a mutation in one of 100 renal ciliopathy genes, and no unifying pathogenic mechanism has been identified. Recently, some NPHPs, including NIMA-related kinase 8 (NEK8) and centrosomal protein 164 (CEP164), have been found to act ...[more]

PMID: 30111592

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Project description:The t-haplotype, a variant form of the t-complex region on mouse chromosome 17, acts as selfish genetic element and is transmitted at high frequencies (> 95%) from heterozygous (t/+) males to their offspring. This phenotype is termed transmission ratio distortion (TRD) and is caused by the interaction of the t-complex responder (Tcr) with several quantitative trait loci (QTL), the t-complex distorters (Tcd1 to Tcd4), all located within the t-haplotype region. Current data suggest that the distorters collectively impair motility of all sperm derived from t/+ males; t-sperm is rescued by the responder, whereas (+)-sperm remains partially dysfunctional. Recently we have identified two distorters as regulators of RHO small G proteins. Here we show that the nucleoside diphosphate kinase gene Nme3 acts as a QTL on TRD. Reduction of the Nme3 dosage by gene targeting of the wild-type allele enhanced the transmission rate of the t-haplotype and phenocopied distorter function. Genetic and biochemical analysis showed that the t-allele of Nme3 harbors a mutation (P89S) that compromises enzymatic activity of the protein and genetically acts as a hypomorph. Transgenic overexpression of the Nme3 t-allele reduced t-haplotype transmission, proving it to be a distorter. We propose that the NME3 protein interacts with RHO signaling cascades to impair sperm motility through hyperactivation of SMOK, the wild-type form of the responder. This deleterious effect of the distorters is counter-balanced by the responder, SMOK(Tcr), a dominant-negative protein kinase exclusively expressed in t-sperm, thus permitting selfish behaviour and preferential transmission of the t-haplotype. In addition, the previously reported association of NME family members with RHO signaling in somatic cell motility and metastasis, in conjunction with our data involving RHO signaling in sperm motility, suggests a functional conservation between mechanisms for motility control in somatic cells and spermatozoa.

Dataset Information

The nucleoside-diphosphate kinase NME3 associates with nephronophthisis proteins and is required for ciliary function during renal development.

Publications

The nucleoside-diphosphate kinase NME3 associates with nephronophthisis proteins and is required for ciliary function during renal development.

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