Wld s requires Nmnatl enzymatic activity and N16- VCP interactions to suppress Wallerian degeneration

Michelle A. Avery, Amy E. Sheehan, Kimberly S. Kerr, Jing Wang, Marc Freeman

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

Slow Wallerian degeneration (Wld s) encodes a chimeric Ube4b/nicotinamide 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 Nmnatl can protect severed axons from autodestruction but at levels significantly lower than Wld s, and enzymedead versions of Nmnatl and Wld s exhibit severely reduced axon-protective function. Interestingly, a 1 6-amino acid N-terminal domain of Wld s3p (termed N1 6) 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 N1 6- 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.

Original languageEnglish (US)
Pages (from-to)501-513
Number of pages13
JournalJournal of Cell Biology
Volume184
Issue number4
DOIs
StatePublished - Feb 23 2009
Externally publishedYes

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Wallerian Degeneration
Nicotinamide Mononucleotide
Axons
Drosophila melanogaster
Drosophila
CDC48 protein
Carrier Proteins
Cytoplasm
Amino Acids
glutamine-synthetase adenylyltransferase
Enzymes

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

Cite this

Wld s requires Nmnatl enzymatic activity and N16- VCP interactions to suppress Wallerian degeneration. / Avery, Michelle A.; Sheehan, Amy E.; Kerr, Kimberly S.; Wang, Jing; Freeman, Marc.

In: Journal of Cell Biology, Vol. 184, No. 4, 23.02.2009, p. 501-513.

Research output: Contribution to journalArticle

Avery, Michelle A. ; Sheehan, Amy E. ; Kerr, Kimberly S. ; Wang, Jing ; Freeman, Marc. / Wld s requires Nmnatl enzymatic activity and N16- VCP interactions to suppress Wallerian degeneration. In: Journal of Cell Biology. 2009 ; Vol. 184, No. 4. pp. 501-513.
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