Holland Sabrina M, Collura Kaitlin M, Ketschek Andrea, Noma Kentaro, Ferguson Toby A, Jin Yishi, Gallo Gianluca, Thomas Gareth M
Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Temple University School of Medicine, Philadelphia, PA 19140;
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;
Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):763-8. doi: 10.1073/pnas.1514123113. Epub 2015 Dec 30.
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.
双亮氨酸拉链激酶（DLK）在神经损伤后的轴突到胞体逆行信号传导中起关键作用。然而，尚不清楚作为一种预测的可溶性激酶，DLK如何传递长距离信号以及为什么同源激酶不能补偿DLK的缺失。在此，我们报告DLK而非同源激酶在其激酶结构域相邻的保守位点发生棕榈酰化。使用短发夹RNA敲低/拯救实验，我们发现棕榈酰化对于感觉轴突中依赖DLK的逆行信号传导至关重要。这种功能重要性源于棕榈酰化的三个新的细胞和分子作用，它将DLK靶向运输囊泡，是组装DLK信号复合物所必需的，并且出乎意料的是，对DLK的激酶活性至关重要。通过同时控制DLK的定位、相互作用和活性，棕榈酰化确保只有与囊泡结合的DLK在神经元中具有活性。这些发现解释了DLK如何特异性介导神经损伤反应，并揭示了一种确保神经元激酶信号特异性的新细胞机制。
