摘要：SummaryC21ORF2andNEK1have 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 withC21ORF2mutation.Graphical AbstractDisplay OmittedHighlights•C21ORF2 is a common substrate of FBXO3 and NEK1•NEK1-mediated phosphorylation of C21ORF2 inhibits its ubiquitylation and degradation•ALS-associated mutant of C21ORF2 is stable owing to hyperphosphorylation•The C21ORF2 mutant protein causes NEK1 accumulation and motor neuron abnormalityBiological Sciences; Molecular Biology; Neuroscience
