NEKL-4 regulates microtubule stability and mitochondrial health inC. elegansciliated neurons

Abstract

AbstractCiliopathies are often caused by defects in the ciliary microtubule core. Glutamylation is abundant in cilia, and its dysregulation may contribute to ciliopathies and neurodegeneration. Mutation of the deglutamylase CCP1 causes infantile-onset neurodegeneration. InC. elegans, ccpp-1loss causes age-related ciliary degradation that is suppressed by mutation in the conserved NEK10 homolognekl-4. NEKL-4 is absent from cilia, yet negatively regulates ciliary stability via an unknown, glutamylation-independent mechanism. We show that NEKL-4 was mitochondria-associated.nekl-4mutants had longer mitochondria, a higher baseline mitochondrial oxidation state, and suppressedccpp-1mutant lifespan extension in response to oxidative stress. A kinase-deadnekl-4(KD)mutant ectopically localized toccpp-1cilia and rescued degenerating microtubule doublet B-tubules. A nondegradablenekl-4(PESTΔ)mutant resembled theccpp-1mutant with dye filling defects and B-tubule breaks. Thenekl-4(PESTΔ)Dyf phenotype was suppressed by mutation in the depolymerizing kinesin-8 KLP-13/KIF19A. We conclude that NEKL-4 influences ciliary stability by activating ciliary kinesins and promoting mitochondrial homeostasis.SummaryNeurodegeneration and ciliary degeneration are caused by mutation of the deglutamylase CCP1/CCPP-1 in humans andC. elegans. The conserved NIMA-related kinase NEKL-4/NEK10 can suppress or promote degeneration in an activity-dependent manner that involves cilia-mitochondria communication and that is independent of glutamylation.