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

Abstract

SummaryDual Leucine-zipper Kinase (DLK, a MAP3K) mediates neuronal responses to diverse injuries and insults via c-Jun N-terminal Kinase (JNK) family Mitogen-activated Protein Kinases (MAPKs). It is unclear why DLK couples to JNKs in mammalian neurons versus other MAPKs, especially because some invertebrate DLK orthologs couple instead to the related p38 family MAPKs. Here we identify two mechanisms that potentially explain this DLK-JNK coupling. First, neural-specific JNK3, but not p38-MAPK, catalyzes positive feedback phosphorylation of DLK that further activates DLK and locks the DLK-JNK3 module in a highly active state. Furthermore, the pro-degenerative JNK2 and JNK3, but not the related JNK1, are endogenously palmitoylated. Moreover, palmitoylation targets both DLK and JNK3 to the same axonal vesicles and JNK3 palmitoylation is essential for pro-degenerative axonal retrograde signaling in vivo. These findings provide insights into DLK-JNK signaling relevant to multiple neuropathological conditions and answer long-standing questions regarding the selective pro-degenerative roles of JNK2/3.

A sticky situation: regulation and function of protein palmitoylation with a spotlight on the axon and axon initial segment

“…DLK activation triggers a MAPK cascade involving its direct MAP2K targets MKK4 and MKK7 and the MAPK JNK, resulting in phosphorylation of the transcription factor c-Jun (166)(167)(168). When DLK is palmitoylated, it localizes to axonal transport vesicles where it complexes with JIP3, MKK4, MKK7, and JNK3 to allow retrograde pro-degenerative signaling in response to injury (Figure 2A and B) (164,165,169). Blocking palmitoylation of DLK completely prevents JNK activation and degeneration both in cultured neurons and in vivo (164,165).…”

“…Blocking palmitoylation of DLK completely prevents JNK activation and degeneration both in cultured neurons and in vivo [ 164 , 165 ]. Indeed, blocking palmitoylation of JNK3 also blocks pro-degenerative phosphorylation of c-Jun following axonal injury [ 169 ]. These findings highlight the critical role palmitoylation plays in neurodegeneration and provide a strong rationale for identifying compounds that inhibit DLK palmitoylation to treat chronic neurodegeneration and acute neuronal injury [ 170 ].…”