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Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):763-8. doi: 10.1073/pnas.1514123113. Epub 2015 Dec 30.

Palmitoylation controls DLK localization, interactions and activity to ensure effective axonal injury signaling.

Author information

1
Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Temple University School of Medicine, Philadelphia, PA 19140;
2
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093; Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093;
3
Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Temple University School of Medicine, Philadelphia, PA 19140; Department of Neurology, Temple University School of Medicine, Philadelphia, PA 19140;
4
Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Temple University School of Medicine, Philadelphia, PA 19140; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140.
5
Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Temple University School of Medicine, Philadelphia, PA 19140; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140 gareth.thomas@temple.edu.

Abstract

Dual leucine-zipper kinase (DLK) is critical for axon-to-soma retrograde signaling following nerve injury. However, it is unknown how DLK, a predicted soluble kinase, conveys long-distance signals and why homologous kinases cannot compensate for loss of DLK. Here, we report that DLK, but not homologous kinases, is palmitoylated at a conserved site adjacent to its kinase domain. Using short-hairpin RNA knockdown/rescue, we find that palmitoylation is critical for DLK-dependent retrograde signaling in sensory axons. This functional importance is because of three novel cellular and molecular roles of palmitoylation, which targets DLK to trafficking vesicles, is required to assemble DLK signaling complexes and, unexpectedly, is essential for DLK's kinase activity. By simultaneously controlling DLK localization, interactions, and activity, palmitoylation ensures that only vesicle-bound DLK is active in neurons. These findings explain how DLK specifically mediates nerve injury responses and reveal a novel cellular mechanism that ensures the specificity of neuronal kinase signaling.

KEYWORDS:

JNK; MAPK; c-Jun; regeneration; trafficking

PMID:
26719418
PMCID:
PMC4725513
DOI:
10.1073/pnas.1514123113
[Indexed for MEDLINE]
Free PMC Article

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