Seminar: The axonal localization of Dual Leucine Zipper Kinase defines its protein-turnover
Subcellular protein localization plays critical roles in diverse neuronal functions. Dual Leucine Zipper Kinase (DLK) mediates neuronal stress responses including neuronal loss in multiple neurodegenerative disorders. DLK is axonally expressed, and its expression is constantly suppressed under normal conditions. However, little is known about how and why DLK is localized in axons. We found that Wallenda (Wnd), the Drosophila ortholog of DLK, is highly enriched in the axon terminals and this localization is necessary for the Highwire-mediated suppression of Wnd protein levels. We further found that a palmitoylation on Wnd plays an essential role in its axonal localization. Inhibiting axonal localization of Wnd resulted in dramatically increased protein levels of Wnd, which led to excessive stress signaling including neuronal loss. Our study demonstrates that subcellular protein localization is coupled with regulated protein turnover in neuronal stress response.