Coupled Control of Distal Axon Integrity and Somal Responses to Axonal Damage by the Palmitoyl Acyltransferase ZDHHC17

Abstract

Highlights d The same enzyme, ZDHHC17, palmitoylates DLK and NMNAT2 d DLK palmitoylation by ZDHHC17 is essential for somal responses to axonal injury d Prolonged loss of ZDHHC17 causes NMNAT-dependent fragmentation of distal axons d Conserved motifs in NMNAT2 and DLK govern their ZDHHC17-dependent regulation

Palmitoylation Couples DLK to JNK3 to Facilitate Pro-degenerative Axon-to-Soma Signaling

“…Finally, we asked whether this differential palmitoylation-dependent distribution might affect retrograde signaling by the DLK-JNK pathway, by assessing the somal response to Optic Nerve Crush (ONC), which requires both palmitoyl-DLK and JNK3 (Fernandes et al 2012; Fernandes et al 2014; Niu et al 2020; Watkins et al 2013; Welsbie et al 2013)(Fig 6D). ONC-induced c-Jun phosphorylation was markedly reduced in JNK3 KO mice and was ‘rescued’ by intravitreally injected HA-JNK3-WT AAV, but not by HA-JNK3-CCSS AAVs (Fig 6E, F).…”

“…We previously reported that DLK palmitoylation is critical for initial responses to axonal injury and, unexpectedly, that this modification is also essential for DLK’s kinase activity in vitro (Holland et al 2016; Niu et al 2020). However, it was unclear from these studies whether palmitoylation controls other aspects of DLK pathway signaling, and why mammalian DLK couples to JNK, rather than to other MAPKs.…”

“…On a practical note, our finding that preventing JNK3 palmitoylation is almost as effective as JNK3 KO in blocking pro-degenerative signaling suggests that this avenue might be pursued therapeutically to reduce the effects of neurodegeneration. The potential of such an approach is increased by findings that signaling by JNK’s upstream activator DLK is also palmitoylation-dependent (Holland et al 2016; Niu et al 2020). Our recent finding that the same palmitoyl acyltransferase (PAT), ZDHHC17, regulates not just DLK and likely JNK3, but also the prosurvival factor Nicotinamide Mononucleotide Adenylytransferase-2 (NMNAT2) complicates this issue.…”

“…Palmitoylation of JNK3 is not required for JNK3 activation in transfected non-neuronal cells, but is essential to target DLK and JNK3 to the same motile trafficking vesicles in neurons and is critical to traffic JNK3 to optic nerve axons in vivo . Finally, using in vivo molecular replacement in JNK3 Knockout (KO) mice, we provide evidence that, similar to the importance of DLK palmitoylation (Niu et al 2020), JNK3 palmitoylation is critical for retrograde signaling following distal optic nerve injury. These findings provide new insights into the control of DLK signaling and answer long-standing questions regarding the molecular basis for selective DLK-JNK coupling and the pro-degenerative roles of JNK2/3.…”

“…We recently reported that covalent modification of DLK with the lipid palmitate, a process called palmitoylation, is critical for somal responses to axonal injury both in cultured neurons and in vivo (Holland et al 2016; Niu et al 2020). One provocative finding from this prior work was that palmitoylation not only controls DLK localization but is also critical for DLK to activate JNK3 in non-neuronal cells (Holland et al 2016), but whether DLK-JNK signaling is similarly palmitoylation-dependent in neurons was not addressed.…”