4.5 Article

The NIMA-family kinase Nek3 regulates microtubule acetylation in neurons

Journal

JOURNAL OF CELL SCIENCE
Volume 122, Issue 13, Pages 2274-2282

Publisher

COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.048975

Keywords

Nek3; NIMA; Microtubule; Cilia; Axon; Neuron; Acetylation; BBS; HDAC6

Categories

Funding

  1. NIH Neuroscience Blueprint Center Core [P30 NS057105]
  2. HOPE Center for Neurological Disorders
  3. National Institutes of Health [CA111966, NS040745, AG13730, K08NS055980]

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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 T475D 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.

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