Rab11 suppresses neuronal stress signaling by localizing Dual leucine zipper kinase to axon terminals for protein turnover

Abstract

SummaryDual 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), theDrosophilaortholog of DLK, is highly enriched in the axon terminals ofDrosophilasensory 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,Rab11loss-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 byRab11loss-of-function. Taken together, these suggest that DLK proteins are constantly transported to axon terminals by Rab11 for protein turnover. Our study demonstrates how subcellular protein localization is coupled to protein turnover for neuronal stress signaling.HighlightsWnd is highly enriched in axon terminals.Wnd protein turnover by Hiw is restricted in the axon terminals.Protein palmitoylation of Wnd and Rab11 activity is essential for Wnd axonal localization.Rab11mutations and defective Wnd palmitoylation impair Wnd protein turnover leading to increased Wnd protein levels and neuronal loss.Inhibiting Wnd activity mitigates neuronal stress response caused byRab11loss-of-function.