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Vol. 17, Issue 3, 1075-1084, March 2006

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The Slow Wallerian Degeneration Protein, Wld^S, Binds Directly to VCP/p97 and Partially Redistributes It within the Nucleus

Heike Laser ^*  , Laura Conforti  , Giacomo Morreale , Till G.M. Mack ^*, Molly Heyer , Jane E. Haley ^||, Thomas M. Wishart ^||, Bogdan Beirowski ^*, Simon A. Walker , Georg Haase ^¶, Arzu Celik ^*, Robert Adalbert , Diana Wagner ^*, Daniela Grumme ^*, Richard R. Ribchester ^||, Markus Plomann ^#, and Michael P. Coleman ^* 

^* Institute for Genetics and Center for Molecular Medicine, University of Cologne, D-50674 Cologne, Germany; The Babraham Institute, Babraham, Cambridge CB2 4AT, United Kingdom; ^|| Division of Neuroscience, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom; ^¶ Avenir Team, INSERM U29, INMED, Luminy, 13273 Marseille Cedex 09, France; and ^# Center for Biochemistry and Center for Molecular Medicine Cologne, University of Cologne, D-50931 Cologne, Germany

Submitted May 2, 2005; Revised November 28, 2005; Accepted December 2, 2005
Monitoring Editor: Jeffrey Brodsky

Slow Wallerian degeneration (Wld^S) mutant mice express a chimeric nuclear protein that protects sick or injured axons from degeneration. The C-terminal region, derived from NAD⁺ synthesizing enzyme Nmnat1, is reported to confer neuroprotection in vitro. However, an additional role for the N-terminal 70 amino acids (N70), derived from multiubiquitination factor Ube4b, has not been excluded. In wild-type Ube4b, N70 is part of a sequence essential for ubiquitination activity but its role is not understood. We report direct binding of N70 to valosin-containing protein (VCP; p97/Cdc48), a protein with diverse cellular roles including a pivotal role in the ubiquitin proteasome system. Interaction with Wld^S targets VCP to discrete intranuclear foci where ubiquitin epitopes can also accumulate. Wld^S lacking its N-terminal 16 amino acids (N16) neither binds nor redistributes VCP, but continues to accumulate in intranuclear foci, targeting its intrinsic NAD⁺ synthesis activity to these same foci. Wild-type Ube4b also requires N16 to bind VCP, despite a more C-terminal binding site in invertebrate orthologues. We conclude that N-terminal sequences of Wld^S protein influence the intranuclear location of both ubiquitin proteasome and NAD⁺ synthesis machinery and that an evolutionary recent sequence mediates binding of mammalian Ube4b to VCP.

Abbreviations used: DRG, dorsal root ganglion; ERAD, endoplasmic reticulum-associated protein degradation; IVTT, in vitro transcription and translation; N16, N-terminal 16 amino acids of Wld^S and Ube4b; N70, N-terminal 70 amino acids of Wld^S and Ube4b; Nmnat1, nicotinamide mononucleotide adenylyltransferase; Ube4b, ubiquitination factor E4b; Ufd2, ubiquitin fusion degradation protein 2; UPS, ubiquitin proteasome system; VCP, valosin-containing protein; Wld^S, slow Wallerian degeneration gene or protein.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

Present address: International University Bremen, D-28759 Bremen, Germany.

Address correspondence to: Michael P. Coleman (michael.coleman{at}bbsrc.ac.uk).

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