Abstract
The small ubiquitin-like modifier (SUMO) is a protein that regulates a wide variety of cellular processes by covalent attachment of SUMO moieties to a diverse array of target proteins. Sumoylation also plays an important role in the replication of many viruses. Previously, we showed that Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a SUMO-ligase, K-bZIP, which catalyzes sumoylation of host and viral proteins. We report here that this virus also encodes a gene that functions as a SUMO-targeting ubiquitin-ligase (STUbL) which preferentially targets sumoylated proteins for degradation. K-Rta, the major transcriptional factor which turns on the entire lytic cycle, was recently found to have ubiquitin ligase activity toward a selected set of substrates. We show in this study that K-Rta contains multiple SIMs (SUMO interacting motif) and binds SUMOs with higher affinity toward SUMO-multimers. Like RNF4, the prototypic cellular STUbL, K-Rta degrades SUMO-2/3 and SUMO-2/3 modified proteins, including promyelocytic leukemia (PML) and K-bZIP. PML-NBs (nuclear bodies) or ND-10 are storage warehouses for sumoylated proteins, which negatively regulate herpesvirus infection, as part of the intrinsic immune response. Herpesviruses have evolved different ways to degrade or disperse PML bodies, and KSHV utilizes K-Rta to inhibit PML-NBs formation. This process depends on K-Rta's ability to bind SUMO, as a K-Rta SIM mutant does not effectively degrade PML. Mutations in the K-Rta Ring finger-like domain or SIM significantly inhibited K-Rta transactivation activity in reporter assays and in the course of viral reactivation. Finally, KSHV with a mutation in the Ring finger-like domain or SIM of K-Rta replicates poorly in culture, indicating that reducing SUMO-conjugates in host cells is important for viral replication. To our knowledge, this is the first virus which encodes both a SUMO ligase and a SUMO-targeting ubiquitin ligase that together may generate unique gene regulatory programs.
Highlights
Sumoylation is recognized as a universal signal transducer, rivaling phosphorylation
We previously described the identification of a viral small ubiquitin-like modifier (SUMO) E3 ligase encoded by Kaposi’s sarcoma-associated herpesvirus (KSHV), which couples SUMO to recipient proteins
We previously reported the identification of the first viral E3 SUMO ligase, K-bZIP, encoded by Kaposi’s sarcoma-associated herpesvirus (KSHV) [14]
Summary
Sumoylation (small ubiquitin-like modification) is recognized as a universal signal transducer, rivaling phosphorylation. It affects most cellular processes including transcription, RNA processing, DNA replication, DNA repair and chromosome segregation [1,2,3,4,5,6,7]. The SUMO/SIM interaction serves to propagate the cellular signals, which are initiated by SUMO conjugation to protein targets catalyzed by E3 SUMO ligases. The SUMO signal is terminated by SUMO deconjugation via SUMO specific proteases (i.e., SENP1, 2, 3, 5 and 6) [15] Another way of SUMO signal attenuation whereby SUMOylated proteins are targeted for degradation has recently been described. A known RNF substrate is SUMO-PML (promyelocytic leukemia), a molecule involved in the formation of PML-nuclear bodies and implicated in the cellular antiviral response and tumor suppression [16,17,18,19]
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