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.
Original languageEnglish
Pages (from-to)1655-1669
Number of pages15
JournalHuman Molecular Genetics
Volume24
Issue number6
DOIs
Publication statusPublished - 15 Mar 2015
Externally publishedYes

Cite this

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.
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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",
month = "3",
day = "15",
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, 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, 15.03.2015, 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 - 2015/3/15

Y1 - 2015/3/15

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

JF - Human Molecular Genetics

SN - 0964-6906

IS - 6

ER -