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J. Virol. doi:10.1128/JVI.01149-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The large tegument protein (ORF64) of the mouse herpesvirus MHV-68 encodes a functional ubiquitin-specific protease, expressed and active in the course of infection

Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142

^* To whom correspondence should be addressed. Email: ploegh{at}wi.mit.edu.

	Abstract

All herpes viruses contain a ubiquitin (Ub)-specific cysteine protease domain embedded within their large tegument protein, based on homology with the corresponding sequences of UL36 from HSV-1 and M48 from MCMV. This type of activity has yet to be demonstrated for cells infected with a herpes virus. By activity-based profiling we show that the large tegument protein encoded by the murine herpes virus (MHV-68) ORF64 (273 kDa) is a functional deubiquitinating protease, as assessed by tandem mass spectrometry of adducts in extracts from MHV-68 infected cells that had been labeled with ubiquitin vinylmethylester, a ubiquitin-based active site-directed probe. The recombinantly expressed amino terminal segment of ORF64 displays deubiquitinating activity towards Ub-AMC in vitro. The findings reported here for MHV-68 ORF64 extend those made for the and the herpesvirus families, and are consistent with an important, conserved enzymatic function of the tegument protein.

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