The palmitoyl acyltransferases ZDHHC5 and ZDHHC8 are uniquely present in DRG axons and control retrograde signaling via the Gp130/JAK/STAT3 pathway
The palmitoyl acyltransferases ZDHHC5 and ZDHHC8 are uniquely present in DRG axons and control retrograde signaling via the Gp130/JAK/STAT3 pathway
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DOI：
10.1074/jbc.ra120.013815
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发表时间：
2020-11-13
影响因子：
4.8
通讯作者：
Thomas, Gareth M.
中科院分区：
文献类型：
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作者：
Collura, Kaitlin M.;Niu, Jingwen;Thomas, Gareth M.
棕榈酰化，用脂质棕榈酸酯修饰蛋白质，是蛋白质靶向和运输的关键调节因子。然而，对催化棕榈酰化的特异性棕榈酰转移酶（PATs）的作用的了解尚不完整。例如，尽管棕榈酰蛋白的远距离运输对于轴突的完整性和轴突到体细胞的逆行信号（轴突发育和损伤反应的关键过程）很重要，但对于神经元轴突中存在哪些pat知之甚少。因此，识别轴突靶向的pat可能为轴突生物学的多个方面提供见解。因此，我们全面确定了哺乳动物背根神经节（DRG）神经元中PATs的亚细胞分布，并令人惊讶地发现，只有ZDHHC5和ZDHHC8两个PATs富集于DRG轴突。Gp130/JAK/STAT3和DLK/JNK通路的信号对轴突损伤反应很重要，我们发现Gp130/JAK/STAT3通路需要ZDHHC5和ZDHHC8，而DLK/JNK通路不需要ZDHHC8。ZDHHC5和ZDHHC8在共转染的非神经元细胞中强烈棕榈酰化Gp130，支持Gp130是ZDHHC5/8直接底物的可能性。在DRG神经元中，Zdhhc5/8 shRNA敲低可降低Gp130棕榈酰化，甚至更显著地降低Gp130表面表达，这可能解释了这些PATs对Gp130依赖性信号传导的重要性。总之，这些发现提供了新的见解亚细胞分布和特定的pat的作用，并揭示了棕榈酰化控制轴突逆行信号的新机制。
Palmitoylation, the modification of proteins with the lipid palmitate, is a key regulator of protein targeting and trafficking. However, knowledge of the roles of specific palmitoyl acyltransferases (PATs), which catalyze palmitoylation, is incomplete. For example, little is known about which PATs are present in neuronal axons, although long-distance trafficking of palmitoyl-proteins is important for axon integrity and for axon-to-soma retrograde signaling, a process critical for axon development and for responses to injury. Identifying axonally targeted PATs might thus provide insights into multiple aspects of axonal biology. We therefore comprehensively determined the subcellular distribution of mammalian PATs in dorsal root ganglion (DRG) neurons and, strikingly, found that only two PATs, ZDHHC5 and ZDHHC8, were enriched in DRG axons. Signals via the Gp130/JAK/STAT3 and DLK/JNK pathways are important for axonal injury responses, and we found that ZDHHC5 and ZDHHC8 were required for Gp130/JAK/STAT3, but not DLK/JNK, axon-to-soma signaling. ZDHHC5 and ZDHHC8 robustly palmitoylated Gp130 in cotransfected nonneuronal cells, supporting the possibility that Gp130 is a direct ZDHHC5/8 substrate. In DRG neurons, Zdhhc5/8 shRNA knockdown reduced Gp130 palmitoylation and even more markedly reduced Gp130 surface expression, potentially explaining the importance of these PATs for Gp130-dependent signaling. Together, these findings provide new insights into the subcellular distribution and roles of specific PATs and reveal a novel mechanism by which palmitoylation controls axonal retrograde signaling.