RRC ID 65290
Author Power KM, Akella JS, Gu A, Walsh JD, Bellotti S, Morash M, Zhang W, Ramadan YH, Ross N, Golden A, Smith HE, Barr MM, O'Hagan R.
Title Mutation of NEKL-4/NEK10 and TTLL genes suppress neuronal ciliary degeneration caused by loss of CCPP-1 deglutamylase function.
Journal PLoS Genet
Abstract Ciliary microtubules are subject to post-translational modifications that act as a "Tubulin Code" to regulate motor traffic, binding proteins and stability. In humans, loss of CCP1, a cytosolic carboxypeptidase and tubulin deglutamylating enzyme, causes infantile-onset neurodegeneration. In C. elegans, mutations in ccpp-1, the homolog of CCP1, result in progressive degeneration of neuronal cilia and loss of neuronal function. To identify genes that regulate microtubule glutamylation and ciliary integrity, we performed a forward genetic screen for suppressors of ciliary degeneration in ccpp-1 mutants. We isolated the ttll-5(my38) suppressor, a mutation in a tubulin tyrosine ligase-like glutamylase gene. We show that mutation in the ttll-4, ttll-5, or ttll-11 gene suppressed the hyperglutamylation-induced loss of ciliary dye filling and kinesin-2 mislocalization in ccpp-1 cilia. We also identified the nekl-4(my31) suppressor, an allele affecting the NIMA (Never in Mitosis A)-related kinase NEKL-4/NEK10. In humans, NEK10 mutation causes bronchiectasis, an airway and mucociliary transport disorder caused by defective motile cilia. C. elegans NEKL-4 localizes to the ciliary base but does not localize to cilia, suggesting an indirect role in ciliary processes. This work defines a pathway in which glutamylation, a component of the Tubulin Code, is written by TTLL-4, TTLL-5, and TTLL-11; is erased by CCPP-1; is read by ciliary kinesins; and its downstream effects are modulated by NEKL-4 activity. Identification of regulators of microtubule glutamylation in diverse cellular contexts is important to the development of effective therapies for disorders characterized by changes in microtubule glutamylation. By identifying C. elegans genes important for neuronal and ciliary stability, our work may inform research into the roles of the tubulin code in human ciliopathies and neurodegenerative diseases.
Volume 16(10)
Pages e1009052
Published 2020-10-1
DOI 10.1371/journal.pgen.1009052
PMID 33064774
PMC PMC7592914
MeSH Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development Caenorhabditis elegans Proteins / genetics* Carboxypeptidases / genetics* Carrier Proteins / genetics Cilia / genetics Cilia / metabolism Glutamic Acid / metabolism Humans Kinesins / genetics Microtubules / genetics Mutation / genetics NIMA-Related Kinases / genetics Nerve Degeneration / genetics* Nerve Degeneration / pathology Neurons / metabolism Neurons / pathology Peptide Synthases / genetics* Protein Processing, Post-Translational / genetics Tubulin / genetics*
C.elegans tm3310 tm3360 tm4059 tm4910