Czarnecki Peter G, Gabriel George C, Manning Danielle K, Sergeev Mikhail, Lemke Kristi, Klena Nikolai T, Liu Xiaoqin, Chen Yu, Li You, San Agustin Jovenal T, Garnaas Maija K, Francis Richard J, Tobita Kimimasa, Goessling Wolfram, Pazour Gregory J, Lo Cecilia W, Beier David R, Shah Jagesh V
1] Department of Systems Biology, Harvard Medical School, 4 Blackfan Circle, HIM 568, Boston, Massachussetts 02115, USA [2] Renal Division, Brigham and Women's Hospital, Boston, Massachussetts 02115, USA [3] Renal Division, Beth Israel Deaconess Medical Center, Boston, Massachussetts 02215, USA.
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Nat Commun. 2015 Jan 20;6:6023. doi: 10.1038/ncomms7023.
The ciliary kinase NEK8 plays a critical role in situs determination and cystic kidney disease, yet its exact function remains unknown. In this study, we identify ANKS6 as a target and activator of NEK8. ANKS6 requires NEK8 for localizing to the ciliary inversin compartment (IC) and activates NEK8 by binding to its kinase domain. Here we demonstrate the functional importance of this interaction through the analysis of two novel mouse mutations, Anks6(Streaker) and Nek8(Roc). Both display heterotaxy, cardiopulmonary malformations and cystic kidneys, a syndrome also characteristic of mutations in Invs and Nphp3, the other known components of the IC. The Anks6(Strkr) mutation decreases ANKS6 interaction with NEK8, precluding NEK8 activation. The Nek8(Roc) mutation inactivates NEK8 kinase function while preserving ANKS6 localization to the IC. Together, these data reveal the crucial role of NEK8 kinase activation within the IC, promoting proper left-right patterning, cardiopulmonary development and renal morphogenesis.
睫状激酶NEK8在左右不对称性决定和多囊肾病中起关键作用，但其确切功能仍不清楚。在本研究中，我们鉴定出ANKS6是NEK8的一个靶点和激活剂。ANKS6需要NEK8才能定位于睫状逆向蛋白区室（IC），并通过与NEK8的激酶结构域结合来激活NEK8。在此，我们通过分析两个新的小鼠突变体Anks6(Streaker)和Nek8(Roc)，证明了这种相互作用的功能重要性。二者均表现出内脏反位、心肺畸形和多囊肾，这种综合征也是IC的其他已知组成部分Invs和Nphp3发生突变的特征。Anks6(Strkr)突变减少了ANKS6与NEK8的相互作用，从而阻止了NEK8的激活。Nek8(Roc)突变使NEK8激酶功能失活，同时保留ANKS6在IC中的定位。这些数据共同揭示了IC内NEK8激酶激活在促进正确的左右模式形成、心肺发育和肾脏形态发生中的关键作用。
