Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.
Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Cell Rep. 2020 Nov 17;33(7):108365. doi: 10.1016/j.celrep.2020.108365.
After optic nerve crush (ONC), the cell bodies and distal axons of most retinal ganglion cells (RGCs) degenerate. RGC somal and distal axon degenerations were previously thought to be controlled by two parallel pathways, involving activation of the kinase dual leucine-zipper kinase (DLK) and loss of the axon survival factor nicotinamide mononucleotide adenylyltransferase-2 (NMNAT2), respectively. Here, we report that palmitoylation of both DLK and NMNAT2 by the palmitoyl acyltransferase ZDHHC17 couples these signals. ZDHHC17-dependent palmitoylation enables DLK-dependent somal degeneration after ONC and also ensures NMNAT-dependent distal axon integrity in healthy optic nerves. We provide evidence that ZDHHC17 also controls survival-versus-degeneration decisions in dorsal root ganglion (DRG) neurons, and we identify conserved motifs in NMNAT2 and DLK that govern their ZDHHC17-dependent regulation. These findings suggest that the control of somal and distal axon integrity should be considered as a single, holistic process, mediated by the concerted action of two palmitoylation-dependent pathways.
视神经挤压（ONC）后，大多数视网膜神经节细胞（RGC）的细胞体和远端轴突都会退化。RGC 细胞体和远端轴突的退化以前被认为是由两条平行的途径控制的，分别涉及激酶双亮氨酸拉链激酶（DLK）的激活和轴突存活因子烟酰胺单核苷酸腺嘌呤二核苷酸转移酶-2（NMNAT2）的丧失。在这里，我们报告由棕榈酰转移酶 ZDHHC17 对 DLK 和 NMNAT2 进行的棕榈酰化将这些信号联系在一起。ZDHHC17 依赖性棕榈酰化使 ONC 后 DLK 依赖性细胞体退化成为可能，并且还确保了健康视神经中 NMNAT 依赖性远端轴突的完整性。我们提供的证据表明，ZDHHC17 还控制背根神经节（DRG）神经元中的存活与退化决策，并且我们确定了 NMNAT2 和 DLK 中的保守基序，这些基序控制它们对 ZDHHC17 的依赖性调节。这些发现表明，应该将细胞体和远端轴突完整性的控制视为一个单一的整体过程，由两条棕榈酰化依赖性途径的协同作用介导。
