MAP9/MAPH-9 supports axonemal microtubule doublets and modulates motor movement

Tran, Michael V.; Khuntsariya, Daria; Fetter, Richard D.; Ferguson, James W.; Wang, Jennifer T.; Long, Alexandra F.; Cote, Lauren E.; Wellard, Stephen R.; Vázquez-Martínez, Nabor; Sallee, Maria D.; Genova, Mariya; Magiera, Maria M.; Eskinazi, Sani; Lee, Jessica D.; Peel, Nina; Janke, Carsten; Stearns, Tim; Shen, Kang; Lansky, Zdenek; Magescas, Jérémy; Feldman, Jessica L.

doi:10.1016/j.devcel.2023.12.001

Cited by 4 publications

(1 citation statement)

References 85 publications

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“…The amphid sensory organ houses 12 sensory neurons, which cannot easily be distinguished using live confocal imaging. The phasmid cilia are structurally comparable to the amphids (Tran et al, 2023), and are easily distinguished as they are the only ciliated neurons in the posterior area of the worm, other than PQR. Thus, for further experiments requiring live imaging, the phasmid neurons were used.…”

Section: Kinase-dead Nekl-4(kd) Suppresses the Ccpp-1δ Dye-filling Ph...mentioning

confidence: 99%

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

Power,

Nguyen,

Silva

et al. 2024

Preprint

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Ciliopathies 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. In C. elegans, ccpp-1 loss causes age-related ciliary degradation that is suppressed by mutation in the conserved NEK10 homolog nekl-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-4 mutants had longer mitochondria, a higher baseline mitochondrial oxidation state, and suppressed ccpp-1 mutant lifespan extension in response to oxidative stress. A kinase-dead nekl-4(KD) mutant ectopically localized to ccpp-1 cilia and rescued degenerating microtubule doublet B-tubules. A nondegradable nekl-4(PEST∆) mutant resembled the ccpp-1 mutant with dye filling defects and B-tubule breaks. The nekl-4(PEST∆) 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.

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Section: Kinase-dead Nekl-4(kd) Suppresses the Ccpp-1δ Dye-filling Ph...mentioning

confidence: 99%

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

Power,

Nguyen,

Silva

et al. 2024

Preprint

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Glutamylation imbalance impairs the molecular architecture of the photoreceptor cilium

Mercey,

Gadadhar,

Magiera

et al. 2024

EMBO J

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Microtubules, composed of conserved α/β-tubulin dimers, undergo complex post-translational modifications (PTMs) that fine-tune their properties and interactions with other proteins. Cilia exhibit several tubulin PTMs, such as polyglutamylation, polyglycylation, detyrosination, and acetylation, with functions that are not fully understood. Mutations in AGBL5, which encodes the deglutamylating enzyme CCP5, have been linked to retinitis pigmentosa, suggesting that altered polyglutamylation may cause photoreceptor cell degeneration, though the underlying mechanisms are unclear. Using super-resolution ultrastructure expansion microscopy (U-ExM) in mouse and human photoreceptor cells, we observed that most tubulin PTMs accumulate at the connecting cilium that links outer and inner photoreceptor segments. Mouse models with increased glutamylation (Ccp5−/− and Ccp1−/−) or loss of tubulin acetylation (Atat1−/−) showed that aberrant glutamylation, but not acetylation loss, disrupts outer segment architecture. This disruption includes exacerbation of the connecting cilium, loss of the bulge region, and destabilization of the distal axoneme. Additionally, we found significant impairment in tubulin glycylation, as well as reduced levels of intraflagellar transport proteins and of retinitis pigmentosa-associated protein RPGR. Our findings indicate that proper glutamylation levels are crucial for maintaining the molecular architecture of the photoreceptor cilium.

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NEKL-4 regulates microtubule stability and mitochondrial health in ciliated neurons

Power,

Nguyen,

Silva

et al. 2024

Journal of Cell Biology

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Ciliopathies 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. In C. elegans, ccpp-1 loss causes age-related ciliary degradation that is suppressed by a mutation in the conserved NEK10 homolog nekl-4. NEKL-4 is absent from cilia, yet it negatively regulates ciliary stability via an unknown, glutamylation-independent mechanism. We show that NEKL-4 was mitochondria-associated. Additionally, nekl-4 mutants had longer mitochondria, a higher baseline mitochondrial oxidation state, and suppressed ccpp-1∆ mutant lifespan extension in response to oxidative stress. A kinase-dead nekl-4(KD) mutant ectopically localized to ccpp-1∆ cilia and rescued degenerating microtubule doublet B-tubules. A nondegradable nekl-4(PEST∆) mutant resembled the ccpp-1∆ mutant with dye-filling defects and B-tubule breaks. The nekl-4(PEST∆) 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.

show abstract

MAP9/MAPH-9 supports axonemal microtubule doublets and modulates motor movement

Cited by 4 publications

References 85 publications

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

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

Glutamylation imbalance impairs the molecular architecture of the photoreceptor cilium

NEKL-4 regulates microtubule stability and mitochondrial health in ciliated neurons

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