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Stress-induced DLK-vesicle assembly acts as local signaling platform that drives kinase activation and neurodegeneration

ABSTRACT: Mitogen-activated protein kinases (MAPKs) drive key signaling cascades during neuronal survival and degeneration. The re-localization of kinases to specific subcellular compartments is a critical mechanism to locally control signaling activity and specificity upon stimulation. However, how MAPK signaling components tightly control their localization remains largely unknown. Here, we systematically analyzed the phosphorylation and membrane localization of all MAPKs expressed in dorsal root ganglia neurons, under control and stress conditions. We found that MAP3K12/ dual leucine zipper kinase (DLK) is the only MAPK that becomes phosphorylated and palmitoylated, and it is recruited to sphingomyelin rich vesicles upon stress. The DLK stress-induced vesicle assembly is essential for kinase activation; blocking DLK-membrane interactions inhibits downstream signaling, while DLK recruitment to ectopic subcellular structures is sufficient to induce kinase activation. We show that the localization of DLK to newly formed vesicles is essential for local signaling and inhibition of membrane internalization blocks DLK activation and protects against neurodegeneration. These data establish vesicular assemblies as dynamically regulated platforms for DLK signaling during neuronal stress responses.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Casper C. Hoogenraad

PROVIDER: MSV000088168 | MassIVE |

REPOSITORIES: MassIVE

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Stress-induced DLK-vesicle assembly acts as local signaling platform that drives kinase activation and neurodegeneration

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