Phosphorylation of hnRNP K by cyclin-dependent kinase 2 controls cytosolic accumulation of TDP-43

Diane Moujalled, Janine L. James, Shu Yang, Katharine Zhang, Clare Duncan, Donia M. Moujalled, Sarah J. Parker, Aphrodite Caragounis, Grace Lidgerwood, Bradley J. Turner, Julie D. Atkin, Alexandra Grubman, Jeffrey R. Liddell, Christian Proepper, Tobias M. Boeckers, Katja M. Kanninen, Ian Blair, Peter J. Crouch, Anthony R. White*

*Corresponding author for this work

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    Abstract

    Cytosolic accumulation of TAR DNA binding protein 43 (TDP-43) is a major neuropathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the mechanisms involved in TDP-43 accumulation remain largely unknown. Previously, we reported that inhibitors of cyclin-dependent kinases (CDKs) prevented cytosolic stress granule accumulation of TDP-43, correlating with depletion of heterogeneous ribonucleoprotein (hnRNP) K from stress granules. In the present study, we further investigated the relationship between TDP-43 and hnRNP K and their control by CDKs. Inhibition of CDK2 abrogated the accumulation of TDP-43 into stress granules. Phosphorylated CDK2 co-localized with accumulated TDP-43 and phosphorylated hnRNP K in stress granules. Inhibition of CDK2 phosphorylation blocked phosphorylation of hnRNP K, preventing its incorporation into stress granules. Due to interaction between hnRNP K with TDP-43, the loss of hnRNP K from stress granules prevented accumulation of TDP-43. Mutation of Ser216 and Ser284 phosphorylation sites on hnRNP K inhibited hnRNP K- and TDP-43-positive stress granule formation in transfected cells. The interaction between hnRNP K and TDP-43 was further confirmed by the loss of TDP-43 accumulation following siRNA-mediated inhibition of hnRNP K expression. A substantial decrease of CDK2 and hnRNP K expression in spinal cord motor neurons in ALS patients demonstrates a potential key role for these proteins in ALS and TDP-43 accumulation, indicating that further investigation of the association between hnRNP K and TDP-43 is warranted. Understanding how kinase activity modulates TDP-43 accumulation may provide new pharmacological targets for disease intervention.

    Original languageEnglish
    Article numberddu578
    Pages (from-to)1655-1669
    Number of pages15
    JournalHuman molecular genetics
    Volume24
    Issue number6
    DOIs
    Publication statusPublished - 15 Mar 2015

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    Moujalled, D., James, J. L., Yang, S., Zhang, K., Duncan, C., Moujalled, D. M., ... White, A. R. (2015). Phosphorylation of hnRNP K by cyclin-dependent kinase 2 controls cytosolic accumulation of TDP-43. Human molecular genetics, 24(6), 1655-1669. [ddu578]. https://doi.org/10.1093/hmg/ddu578