Identification and characterization of a novel deubiquitinating activity conserved within the herpesvirus large tegument proteins
By: by Lisa Marie Kattenhorn
Published: 2007
Language: eng
Number of pages: 106
Description: This work describes the proteomic characterization of murine cytomegalovirus virions, and the identification of a novel deubiquitinating enzyme within the amino terminus of the largest tegument protein. We have discovered a ubiquitin-specific cysteine protease encoded within the N-terminal ∼500 residues of the UL36 gene product, the largest (3164 aa) tegument protein of herpes simplex virus 1 (HSV-1). The protease, UL36 USP , bears no homology to known deubiquitinating enzymes (DUBs) or ubiquitin binding proteins. Sequence alignment of the large tegument proteins across the family Herpesviridae indicates conservation of key catalytic residues amongst these viruses. Biochemical analysis demonstrates that UL36 USP exhibits hydrolytic activity toward Ub-AMC and ubiquitinated branched peptides in vitro . In addition, recombinant UL36 USP can cleave polyubiquitin chains, and may have a preference for Lys 48 linkages.

Enzymatic activity is conserved in Marek's disease virus (MDV), a tumorigenic herpesvirus in the same subfamily as HSV-1. A single amino acid substitution, abolishing the USP activity of the MDV large tegument protein, diminishes MDV replication in vivo, as well as severely limiting the oncogenic potential of the virus. The herpesvirus USP may thus be required not only to maintain a foothold in the immunocompetent host, but also to contribute to malignant outgrowths. We demonstrate that the ubiquitin-specific protease activity is similarly conserved in murine cytomegalovirus (MCMV), a betaherpesvirus. Replication of a mutant lacking the homologous USP domain of the MCMV large tegument protein, M48, is compromised at Day 7-8 in mouse liver and spleen, and at Day 14 in mouse salivary glands. Potential roles for this herpesvirus protease in the viral life cycle are discussed.
Notes: "May 2007"

Thesis (Ph.D., Division of Medical Sciences (Virology))--Harvard University, 2007.

Includes bibliographical references.