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

    Research output: Contribution to journalArticleResearchpeer-review

    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.

    LanguageEnglish
    Article numberddu578
    Pages1655-1669
    Number of pages15
    JournalHuman molecular genetics
    Volume24
    Issue number6
    DOIs
    Publication statusPublished - 2015

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    Cyclin-Dependent Kinase 2
    Ribonucleoproteins
    DNA-Binding Proteins
    Phosphorylation
    Amyotrophic Lateral Sclerosis
    Cyclin-Dependent Kinases
    Frontotemporal Lobar Degeneration
    Motor Neurons

    Cite this

    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
    Moujalled, Diane ; James, Janine L. ; Yang, Shu ; Zhang, Katharine ; Duncan, Clare ; Moujalled, Donia M. ; Parker, Sarah J. ; Caragounis, Aphrodite ; Lidgerwood, Grace ; Turner, Bradley J. ; Atkin, Julie D. ; Grubman, Alexandra ; Liddell, Jeffrey R. ; Proepper, Christian ; Boeckers, Tobias M. ; Kanninen, Katja M. ; Blair, Ian ; Crouch, Peter J. ; White, Anthony R. / Phosphorylation of hnRNP K by cyclin-dependent kinase 2 controls cytosolic accumulation of TDP-43. In: Human molecular genetics. 2015 ; Vol. 24, No. 6. pp. 1655-1669.
    @article{d20d1f80bdbc4fde9800479ea20390f5,
    title = "Phosphorylation of hnRNP K by cyclin-dependent kinase 2 controls cytosolic accumulation of TDP-43",
    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.",
    author = "Diane Moujalled and James, {Janine L.} and Shu Yang and Katharine Zhang and Clare Duncan and Moujalled, {Donia M.} and Parker, {Sarah J.} and Aphrodite Caragounis and Grace Lidgerwood and Turner, {Bradley J.} and Atkin, {Julie D.} and Alexandra Grubman and Liddell, {Jeffrey R.} and Christian Proepper and Boeckers, {Tobias M.} and Kanninen, {Katja M.} and Ian Blair and Crouch, {Peter J.} and White, {Anthony R.}",
    year = "2015",
    doi = "10.1093/hmg/ddu578",
    language = "English",
    volume = "24",
    pages = "1655--1669",
    journal = "Human molecular genetics",
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    Moujalled, D, James, JL, Yang, S, Zhang, K, Duncan, C, Moujalled, DM, Parker, SJ, Caragounis, A, Lidgerwood, G, Turner, BJ, Atkin, JD, Grubman, A, Liddell, JR, Proepper, C, Boeckers, TM, Kanninen, KM, Blair, I, Crouch, PJ & White, AR 2015, 'Phosphorylation of hnRNP K by cyclin-dependent kinase 2 controls cytosolic accumulation of TDP-43', Human molecular genetics, vol. 24, no. 6, ddu578, pp. 1655-1669. https://doi.org/10.1093/hmg/ddu578

    Phosphorylation of hnRNP K by cyclin-dependent kinase 2 controls cytosolic accumulation of TDP-43. / Moujalled, Diane; James, Janine L.; Yang, Shu; Zhang, Katharine; Duncan, Clare; Moujalled, Donia M.; Parker, Sarah J.; Caragounis, Aphrodite; Lidgerwood, Grace; Turner, Bradley J.; Atkin, Julie D.; Grubman, Alexandra; Liddell, Jeffrey R.; Proepper, Christian; Boeckers, Tobias M.; Kanninen, Katja M.; Blair, Ian; Crouch, Peter J.; White, Anthony R.

    In: Human molecular genetics, Vol. 24, No. 6, ddu578, 2015, p. 1655-1669.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Phosphorylation of hnRNP K by cyclin-dependent kinase 2 controls cytosolic accumulation of TDP-43

    AU - Moujalled, Diane

    AU - James, Janine L.

    AU - Yang, Shu

    AU - Zhang, Katharine

    AU - Duncan, Clare

    AU - Moujalled, Donia M.

    AU - Parker, Sarah J.

    AU - Caragounis, Aphrodite

    AU - Lidgerwood, Grace

    AU - Turner, Bradley J.

    AU - Atkin, Julie D.

    AU - Grubman, Alexandra

    AU - Liddell, Jeffrey R.

    AU - Proepper, Christian

    AU - Boeckers, Tobias M.

    AU - Kanninen, Katja M.

    AU - Blair, Ian

    AU - Crouch, Peter J.

    AU - White, Anthony R.

    PY - 2015

    Y1 - 2015

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=84936088075&partnerID=8YFLogxK

    U2 - 10.1093/hmg/ddu578

    DO - 10.1093/hmg/ddu578

    M3 - Article

    VL - 24

    SP - 1655

    EP - 1669

    JO - Human molecular genetics

    T2 - Human molecular genetics

    JF - Human molecular genetics

    SN - 0964-6906

    IS - 6

    M1 - ddu578

    ER -