Modulation of global SUMOylation by Kaposi's sarcoma-associated herpesvirus and its effects on viral gene expression.

Some viruses have evolved to exploit the host SUMOylation system to regulate their own replication. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes K-bZIP, a SUMO E3 ligase catalyzing the SUMOylation of viral and host proteins. KSHV also encodes replication and transcriptional activator (RTA), a SUMO-targeted ubiquitin ligase catalyzing the ubiquitination of SUMOylated proteins and targeting them for degradation. Using chronic KSHV-infected TRE × BCBL-1 RTA cells, the expression kinetics of K-bZIP and RTA, and the global SUMOylation level were detected. The endogenous K-bZIP protein increased dramatically after the induction of the RTA gene that is tetracycline responsive, but then decreased rapidly after peaking at 8 h post tetracycline treatment. Consistently, the global SUMO-conjugated proteins increased and remained at high levels until 8 h, and decreased afterward, correlating with the expression kinetics of RTA and K-bZIP. In luciferase reporter assays, transfection of 293T cells with SUMO2 expression plasmid reduced the RTA transactivations of immediate-early genes k8, orf45, and orf50, but enhanced the RTA transactivations of other viral genes including orf57, pan, k2, orf8, and orf73. These results indicated that KSHV might regulate gene expression and viral replication schedule through modulation of the global SUMOylation level, probably via RTA, and RTA-regulated K-bZIP.