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bioRxiv · 10.1101/2023.04.18.537392

The axonal localization of Dual Leucine Zipper Kinase defines its protein-turnover

Kim, S.·Quagraine, Y.·Singh, M.·Kim, J. H.
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Abstract

Dual Leucine Zipper Kinase (DLK) mediates multiple neuronal stress responses, and its expression levels are constantly suppressed to prevent excessive stress signaling. We found that Wallenda (Wnd), the Drosophila ortholog of DLK, is highly enriched in the axon terminals of Drosophila sensory neurons in vivo and that this subcellular localization is necessary for Highwire-mediated Wnd protein turnover under normal conditions. Our structure-function analysis found that Wnd palmitoylation is essential for its axon terminal localization. Palmitoylation-defective Wnd accumulated in neuronal cell bodies, exhibited dramatically increased protein expression levels, and triggered excessive neuronal stress responses. Defective intracellular transport is implicated in neurodegenerative conditions. Comprehensive dominant-negative Rab protein screening identified Rab11 as an essential factor for Wnd localization in axon terminals. Consequently, Rab11 loss-of-function increased the protein levels of Wnd and induced neuronal stress responses. Inhibiting Wnd activity significantly ameliorated neuronal loss and c-Jun N-terminal kinase signaling triggered by Rab11 loss-of-function. Taken together, these suggest that DLK proteins are constantly transported to axon terminals for protein turnover and a failure of such transport can lead to neuronal loss. Our study demonstrates how subcellular protein localization is coupled to protein turnover for neuronal stress signaling. HighlightsO_LIWnd is highly enriched in axon terminals. C_LIO_LIWnd protein turnover by Hiw is restricted in the axon terminals. C_LIO_LIProtein palmitoylation of Wnd and Rab11 activity is essential for Wnd axonal localization. C_LIO_LIRab11 mutations and defective Wnd palmitoylation impair Wnd protein turnover leading to increased Wnd protein levels and neuronal loss. C_LIO_LIInhibiting Wnd activity mitigates neuronal stress response caused by Rab11 loss-of-function. C_LI

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Kim, S., Quagraine, Y., Singh, M., Kim, J. H.. 2023-04-19. The axonal localization of Dual Leucine Zipper Kinase defines its protein-turnover. https://doi.org/10.1101/2023.04.18.537392

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