WldS requires Nmnat1 enzymatic activity and N16–VCP interactions to suppress Wallerian degeneration

摘要

Slow Wallerian degeneration (Wld^S) encodes a chimeric Ube4bicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) fusion protein that potently suppresses Wallerian degeneration, but the mechanistic action of Wld^S remains controversial. In this study, we characterize Wld^S-mediated axon protection in vivo using Drosophila melanogaster. We show that Nmnat1 can protect severed axons from autodestruction but at levels significantly lower than Wld^S, and enzyme-dead versions of Nmnat1 and Wld^S exhibit severely reduced axon-protective function. Interestingly, a 16–amino acid N-terminal domain of Wld^S (termed N16) accounts for the differences in axon-sparing activity between Wld^S and Nmnat1, and N16-dependent enhancement of Nmnat1-protective activity in Wld^S requires the N16-binding protein valosin-containing protein (VCP)/TER94. Thus, Wld^S-mediated suppression of Wallerian degeneration results from VCP–N16 interactions and Nmnat1 activity converging in vivo. Surprisingly, mouse Nmnat3, a mitochondrial Nmnat enzyme that localizes to the cytoplasm in Drosophila cells, protects severed axons at levels indistinguishable from Wld^S. Thus, nuclear Nmnat activity does not appear to be essential for Wld^S-like axon protection.