Distinct functions of the dual leucine zipper kinase depending on its subcellular localization

TY - JOUR

T1 - Distinct functions of the dual leucine zipper kinase depending on its subcellular localization

AU - Wallbach, Manuel

AU - Duque Escobar, Jorge

AU - Babaeikelishomi, Rohollah

AU - Stahnke, Marie-Jeannette

AU - Blume, Roland

AU - Schröder, Sabine

AU - Kruegel, Jenny

AU - Maedler, Kathrin

AU - Kluth, Oliver

AU - Kehlenbach, Ralph H

AU - Miosge, Nicolai

AU - Oetjen, Elke

N1 - Copyright © 2016 Elsevier Inc. All rights reserved.

PY - 2016/4

Y1 - 2016/4

N2 - The dual leucine zipper kinase DLK induces β-cell apoptosis by inhibiting the transcriptional activity conferred by the β-cell protective transcription factor cAMP response element binding protein CREB. This action might contribute to β-cell loss and ultimately diabetes. Within its kinase domain DLK shares high homology with the mixed lineage kinase (MLK) 3, which is activated by tumor necrosis factor (TNF) α and interleukin (IL)-1β, known prediabetic signals. In the present study, the regulation of DLK in β-cells by these cytokines was investigated. Both, TNFα and IL-1β induced the nuclear translocation of DLK. Mutations within a putative nuclear localization signal (NLS) prevented basal and cytokine-induced nuclear localization of DLK and binding to the importin receptor importin α, thereby demonstrating a functional NLS within DLK. DLK NLS mutants were catalytically active as they phosphorylated their down-stream kinase c-Jun N-terminal kinase to the same extent as DLK wild-type but did neither inhibit CREB-dependent gene transcription nor transcription conferred by the promoter of the anti-apoptotic protein BCL-xL. In addition, the β-cell apoptosis-inducing effect of DLK was severely diminished by mutation of its NLS. In a murine model of prediabetes, enhanced nuclear DLK was found. These data demonstrate that DLK exerts distinct functions, depending on its subcellular localization and thus provide a novel level of regulating DLK action. Furthermore, the prevention of the nuclear localization of DLK as induced by prediabetic signals with consecutive suppression of β-cell apoptosis might constitute a novel target in the therapy of diabetes mellitus.

AB - The dual leucine zipper kinase DLK induces β-cell apoptosis by inhibiting the transcriptional activity conferred by the β-cell protective transcription factor cAMP response element binding protein CREB. This action might contribute to β-cell loss and ultimately diabetes. Within its kinase domain DLK shares high homology with the mixed lineage kinase (MLK) 3, which is activated by tumor necrosis factor (TNF) α and interleukin (IL)-1β, known prediabetic signals. In the present study, the regulation of DLK in β-cells by these cytokines was investigated. Both, TNFα and IL-1β induced the nuclear translocation of DLK. Mutations within a putative nuclear localization signal (NLS) prevented basal and cytokine-induced nuclear localization of DLK and binding to the importin receptor importin α, thereby demonstrating a functional NLS within DLK. DLK NLS mutants were catalytically active as they phosphorylated their down-stream kinase c-Jun N-terminal kinase to the same extent as DLK wild-type but did neither inhibit CREB-dependent gene transcription nor transcription conferred by the promoter of the anti-apoptotic protein BCL-xL. In addition, the β-cell apoptosis-inducing effect of DLK was severely diminished by mutation of its NLS. In a murine model of prediabetes, enhanced nuclear DLK was found. These data demonstrate that DLK exerts distinct functions, depending on its subcellular localization and thus provide a novel level of regulating DLK action. Furthermore, the prevention of the nuclear localization of DLK as induced by prediabetic signals with consecutive suppression of β-cell apoptosis might constitute a novel target in the therapy of diabetes mellitus.

KW - Animals

KW - Apoptosis

KW - Cell Line

KW - Cell Nucleus

KW - Cyclic AMP Response Element-Binding Protein

KW - Diabetes Mellitus, Experimental

KW - Insulin-Secreting Cells

KW - Interleukin-1beta

KW - JNK Mitogen-Activated Protein Kinases

KW - MAP Kinase Kinase Kinases

KW - Mice

KW - Mutation

KW - Protein Transport

KW - Tumor Necrosis Factor-alpha

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.cellsig.2016.01.002

DO - 10.1016/j.cellsig.2016.01.002

M3 - SCORING: Journal article

C2 - 26776303

VL - 28

SP - 272

EP - 283

JO - CELL SIGNAL

JF - CELL SIGNAL

SN - 0898-6568

IS - 4

ER -