title: Palmitoylation controls DLK localization, interactions and activity to ensure effective axonal injury signaling.
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.
authors.affiliation: Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Temple University School of Medicine, Philadelphia, PA 19140;
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Temple University School of Medicine, Philadelphia, PA 19140;
authors.forename: Kaitlin M
authors.initials: KM
authors.lastname: Collura
authors.affiliation: Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Temple University School of Medicine, Philadelphia, PA 19140;
authors.forename: Andrea
authors.initials: A
authors.lastname: Ketschek
authors.affiliation: 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;
authors.forename: Kentaro
authors.initials: K
authors.lastname: Noma
authors.affiliation: 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;
authors.forename: Toby A
authors.initials: TA
authors.lastname: Ferguson
authors.affiliation: 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;
authors.forename: Yishi
authors.initials: Y
authors.lastname: Jin
authors.affiliation: 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.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gallo
authors.affiliation: 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.
authors.forename: Gareth M
authors.initials: GM
authors.lastname: Thomas
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology*; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism*; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005456:Fluorescent Dyes / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D054878:Lipoylation; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000378:metabolism*; D044085:Microfluidics; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011984:Sensory Receptor Cells / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D022161:Transport Vesicles / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D005456:Fluorescent Dyes; D034741:RNA, Small Interfering; C498050:DLK-1 protein, C elegans; D020930:MAP Kinase Kinase Kinases; C090757:mitogen-activated protein kinase kinase kinase 12
keywords: JNK; MAPK; c-Jun; regeneration; trafficking