The NIMA-family kinase Nek3 regulates microtubule acetylation in neurons.
NIMA-related kinases (Neks) belong to a large family of Ser/Thr kinases that have critical roles in coordinating microtubule dynamics during ciliogenesis and mitotic progression. The Nek kinases are also expressed in neurons, whose axonal projections are, similarly to cilia, microtubule-abundant structures that extend from the cell body. We therefore investigated whether Nek kinases have additional, non-mitotic roles in neurons. We found that Nek3 influences neuronal morphogenesis and polarity through effects on microtubules. Nek3 is expressed in the cytoplasm and axons of neurons and is phosphorylated at Thr475 located in the C-terminal PEST domain, which regulates its catalytic activity. Although exogenous expression of wild-type or phosphomimic (T475D) Nek3 in cultured neurons has no discernible impact, expression of a phospho-defective mutant (T475A) or PEST-truncated Nek3 leads to distorted neuronal morphology with disturbed polarity and deacetylation of microtubules via HDAC6 in its kinase-dependent manner. Thus, the phosphorylation at Thr475 serves as a regulatory switch that alters Nek3 function. The deacetylation of microtubules in neurons by unphosphorylated Nek3 raises the possibility that it could have a role in disorders where axonal degeneration is an important component.
Chang
Jufang
J
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Baloh
Robert H
RH
Milbrandt
Jeffrey
J
D000107:Acetylation; D000813:Anilides / Q000378:metabolism; D000818:Animals; D016764:Cell Polarity; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D000072379:NIMA-Related Kinases; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
D000813:Anilides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020033:Protein Isoforms; D014404:Tubulin; C474316:tubacin; D013912:Threonine; C012589:trichostatin A; D000072379:NIMA-Related Kinases; C089442:Nek3 protein, mouse; D017346:Protein Serine-Threonine Kinases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases