The nucleoside-diphosphate kinase NME3 associates with nephronophthisis proteins and is required for ciliary function during renal development.
The nucleoside-diphosphate kinase NME3 associates with nephronophthisis proteins and is required for ciliary function during renal development.
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DOI：
10.1074/jbc.ra117.000847
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发表时间：
2018-09-28
期刊：
影响因子：
--
通讯作者：
Lienkamp SS
中科院分区：
文献类型：
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作者：
Hoff S;Epting D;Falk N;Schroda S;Braun DA;Halbritter J;Hildebrandt F;Kramer-Zucker A;Bergmann C;Walz G;Lienkamp SS
肾结核（NPH）是一种常染色体隐性遗传性肾脏疾病，可导致儿童和年轻人的肾衰竭。相应基因的蛋白产物（NPHPs）定位于初级纤毛或其附属物中。只有大约70%的受影响的个体在100个肾纤毛病变基因中的一个中具有突变，并且没有统一的致病机制被确定。最近，一些NPHPs，包括NIMA相关激酶8（NEK 8）和中心体蛋白164（CEP 164），已被发现在DNA损伤反应途径中起作用，并有助于基因组的稳定性。在这里，我们表明，NME/NM 23核苷二磷酸激酶3（NME 3），最近被发现促进DNA修复机制结合到几个NPHPs，包括NEK 8，CEP 164，和锚蛋白重复和无菌α基序结构域6（ANKS 6）。斑马鱼和非洲爪蟾nme 3缺失导致典型的纤毛病变相关表型，如肾畸形和左右不对称缺陷。我们进一步发现，内源性NME 3定位于基体，并且它还与中心体蛋白如NEK 6相关，其在DNA损伤后调节细胞周期停滞。在两种脊椎动物体内模型中NME 3耗竭的纤毛病典型表现、NME 3与经验证的NPHPs的生物化学关联及其在基体中的定位揭示了NME 3在纤毛功能中的作用。我们的结论是，NME 3基因突变可能会加重在人类中观察到的纤毛病变表型。
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.