Palmitoylation of p75 neurotrophin receptor is required for retrograde regressive signaling

Target-derived neurotrophins regulate neuronal survival and pruning via retrograde signaling. Unlike Trk receptors, which are transported as transmembrane proteins, the p75 neurotrophin receptor (p75NTR) undergoes regulated intramembrane proteolysis to release a soluble intracellular domain (ICD) that must somehow associate with axonal endosomes for retrograde transport. Here, we identify palmitoylation of a conserved juxta membrane cysteine (C281) as a critical requirement for this process. In sympathetic neurons, we demonstrate that p75NTR palmitoylation is dispensable for surface trafficking and proteolytic cleavage but is strictly required for ligand-induced internalization and the biogenesis of p75ICD-positive signaling endosomes. Consequently, blocking palmitoylation, either pharmacologically or via a palmitoylation-deficient C281A mutation, prevents the accumulation of p75ICD in axonal endosomes and blocks axon-initiated apoptosis. In vivo, C281A knock-in mice exhibit reduced developmental apoptosis of sympathetic neurons, similar to p75NTR deletion. These findings define palmitoylation as an essential checkpoint that couples p75NTR cleavage to endosomal segregation, thereby enabling the long-distance transmission of regressive signals.