Watanabe Yasuaki, Nakagawa Tadashi, Akiyama Tetsuya, Nakagawa Makiko, Suzuki Naoki, Warita Hitoshi, Aoki Masashi, Nakayama Keiko
Department of Neurology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8575, Japan; Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8575, Japan.
Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8575, Japan.
iScience. 2020 Aug 21;23(9):101491. doi: 10.1016/j.isci.2020.101491.
C21ORF2 and NEK1 have been identified as amyotrophic lateral sclerosis (ALS)-associated genes. Both genes are also mutated in certain ciliopathies, suggesting that they might contribute to the same signaling pathways. Here we show that FBXO3, the substrate receptor of an SCF ubiquitin ligase complex, binds and ubiquitylates C21ORF2, thereby targeting it for proteasomal degradation. C21ORF2 stabilizes the kinase NEK1, with the result that loss of FBXO3 stabilizes not only C21ORF2 but also NEK1. Conversely, NEK1-mediated phosphorylation stabilizes C21ORF2 by attenuating its interaction with FBXO3. We found that the ALS-associated V58L mutant of C21ORF2 is more susceptible to phosphorylation by NEK1, with the result that it is not ubiquitylated by FBXO3 and therefore accumulates together with NEK1. Expression of C21ORF2(V58L) in motor neurons induced from mouse embryonic stem cells impaired neurite outgrowth. We suggest that inhibition of NEK1 activity is a potential therapeutic approach to ALS associated with C21ORF2 mutation.
C21ORF2和NEK1已被确定为与肌萎缩侧索硬化症（ALS）相关的基因。这两个基因在某些纤毛病中也发生了突变，表明它们可能参与相同的信号通路。在这里，我们表明，SCF泛素连接酶复合物的底物受体FBXO3与C21ORF2结合并使其泛素化，从而将其靶向蛋白酶体降解。C21ORF2使激酶NEK1稳定，结果是FBXO3的缺失不仅使C21ORF2稳定，也使NEK1稳定。相反，NEK1介导的磷酸化通过减弱C21ORF2与FBXO3的相互作用来使其稳定。我们发现，与ALS相关的C21ORF2的V58L突变体更容易被NEK1磷酸化，结果是它不会被FBXO3泛素化，因此与NEK1一起积累。C21ORF2（V58L）在从小鼠胚胎干细胞诱导的运动神经元中的表达损害了神经突的生长。我们认为，抑制NEK1活性是治疗与C21ORF2突变相关的ALS的一种潜在治疗方法。
