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.
authors.affiliation: Department of Pathology and.
authors.forename: Diane
authors.initials: D
authors.lastname: Moujalled
authors.affiliation: Department of Pathology and.
authors.forename: Janine L
authors.initials: JL
authors.lastname: James
authors.affiliation: The Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia.
authors.forename: Shu
authors.initials: S
authors.lastname: Yang
authors.affiliation: The Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia.
authors.forename: Katharine
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Pathology and.
authors.forename: Clare
authors.initials: C
authors.lastname: Duncan
authors.affiliation: Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, VIC 3052, Australia.
authors.forename: Donia M
authors.initials: DM
authors.lastname: Moujalled
authors.affiliation: Department of Pathology and.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Parker
authors.affiliation: Department of Pathology and.
authors.forename: Aphrodite
authors.initials: A
authors.lastname: Caragounis
authors.affiliation: Department of Pathology and.
authors.forename: Grace
authors.initials: G
authors.lastname: Lidgerwood
authors.affiliation: Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Turner
authors.affiliation: The Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia.
authors.forename: Julie D
authors.initials: JD
authors.lastname: Atkin
authors.affiliation: Department of Pathology and.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Grubman
authors.affiliation: Department of Pathology and.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Liddell
authors.affiliation: Anatomy and Cell Biology, University of Ulm, Albert-Einstein Allee 11, 89081 Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Proepper
authors.affiliation: Anatomy and Cell Biology, University of Ulm, Albert-Einstein Allee 11, 89081 Ulm, Germany.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, Laboratory of Molecular Brain Research, University of Eastern Finland, Kuopio, Finland.
authors.forename: Katja M
authors.initials: KM
authors.lastname: Kanninen
authors.affiliation: The Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: Blair
authors.affiliation: Department of Pathology and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.affiliation: Department of Pathology and arwhite@unimelb.edu.au.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D010766:Phosphorylation
chemical_list: D004268:DNA-Binding Proteins; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D051357:Cyclin-Dependent Kinase 2