Abstract
Small Ubiquitin-related MOdifier (SUMO) modification was initially identified as a reversible post-translational modification that affects the regulation of diverse cellular processes, including signal transduction, protein trafficking, chromosome segregation, and DNA repair. Increasing evidence suggests that the SUMO system also plays an important role in regulating chromatin organization and transcription. It is thus not surprising that double-stranded DNA viruses, such as Kaposi’s sarcoma-associated herpesvirus (KSHV), have exploited SUMO modification as a means of modulating viral chromatin remodeling during the latent-lytic switch. In addition, SUMO regulation allows the disassembly and assembly of promyelocytic leukemia protein-nuclear bodies (PML-NBs), an intrinsic antiviral host defense, during the viral replication cycle. Overcoming PML-NB-mediated cellular intrinsic immunity is essential to allow the initial transcription and replication of the herpesvirus genome after de novo infection. As a consequence, KSHV has evolved a way as to produce multiple SUMO regulatory viral proteins to modulate the cellular SUMO environment in a dynamic way during its life cycle. Remarkably, KSHV encodes one gene product (K-bZIP) with SUMO-ligase activities and one gene product (K-Rta) that exhibits SUMO-targeting ubiquitin ligase (STUbL) activity. In addition, at least two viral products are sumoylated that have functional importance. Furthermore, sumoylation can be modulated by other viral gene products, such as the viral protein kinase Orf36. Interference with the sumoylation of specific viral targets represents a potential therapeutic strategy when treating KSHV, as well as other oncogenic herpesviruses. Here, we summarize the different ways KSHV exploits and manipulates the cellular SUMO system and explore the multi-faceted functions of SUMO during KSHV’s life cycle and pathogenesis.
Highlights
K-Rta, a lytic gene product with SUMO-targeting ubiquitin ligase (STUbL) activity, which preferentially catalyzes the degradation of Small Ubiquitin-related MOdifier (SUMO)-2/3 and sumoylated proteins including PML [22]
K-bZIP, a lytic gene product with SUMO E3 ligase activity [18], which is a strong transcriptional repressor and catalyzes the sumoylation of host chromatin remodeling proteins, as well as those involved in innate immunity
LANA, a latent protein with histone H2B sumoylation activity, which is the pivotal protein involved in latency maintenance and malignant transformation
Summary
SUMO has been found in all eukaryotes. There are three major protein conjugating SUMO isoforms in mammals. Viruses target the SUMO pathway by encoding proteins that interact with various components of the pathway in order to modulate their enzyme activities. In addition to targeting cellular SUMO machinery, a few viruses encode viral proteins that have activities analogous to sumoylation enzymes including both SUMO E3 ligase and SUMO-targeted ubiquitin ligase (STUbL). The first identified viral SUMO E3 ligase, K-bZIP, is encoded by KSHV and shows. The protein E1B-55K from HAdV5 is another viral SUMO E3 ligase that shows specificity toward SUMO-1 [19,20]. There has been no report describing viral proteins that have activities analogous to SUMO E1 activating enzyme (SAE1/SAE2), SUMO E2 conjugating enzyme (Ubc9), or SENP
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