Identification of a novel higher molecular weight isoform of USP7/HAUSP that interacts with the Herpes simplex virus type-1 immediate early protein ICPO

The Herpes simplex virus type-1 (HSV-1) regulatory protein ICPO, a RING-finger E3 ubiquitin ligase, stimulates the onset of viral lyric replication and the reactivation of quiescent vital genomes from latency. Like many ubiquitin ligases ICPO induces its own ubiquitination, a process that can lead to its proteasome-dependent degradation. ICPO counteracts this activity by recruiting the cellular ubiquitin-specific protease USP7/HAUSP. Here we show that ICPO can also interact with a previously unidentified isoform of USP7 (termed here USP7(beta)). This isoform is not a predominantly ubiquitinated, SUMO-modified, or phosphorylated species of USP7 but is constitutively expressed in a number of different cell types. Like USP7, USP7(beta) binds specifically to an electrophilic ubiquitin probe, indicating that it contains an accessible catalytic core with potential ubiquitin-protease activity. The interaction formed between ICPO and USP7(beta) requires ICPO to have an intact USP7-binding domain and results in its susceptibility to ICPO-mediated degradation during HSV-1 infection. (C) 2008 Elsevier B.V. All rights reserved.