Abstract
KSHV latency can be envisioned as an outcome that is balanced between factors that promote viral gene expression and lytic replication against those that facilitate gene silencing and establish or maintain latency. A large body of work has focused on the activities of the key viral regulatory proteins involved in KSHV latent or lytic states. Moreover, recent studies have also begun to document the importance of epigenetic landscape evolution of the KSHV viral genome during latency and reactivation. However, one area of KSHV molecular virology that remains largely unanswered is the precise role of post-translational modifications on the activities of viral factors that function during latency and reactivation. In this review, we will summarize the post-translational modifications associated with three viral factors whose activities contribute to the viral state. The viral proteins discussed are the two major KSHV encoded transcription factors, K-Rta (KSHV replication and transcriptional activator) and K-bZIP (KSHV basic leucine zipper) and the viral latency-associated nuclear antigen (LANA). A special emphasis will be placed on the role of the sumoylation pathway in the modulation of the KSHV lifecycle. Newly uncovered small ubiquitin-like modifier (SUMO)-associated properties of LANA and K-Rta will also be presented, namely LANA histone targeting SUMO E3 ligase activity and K-Rta SUMO-targeted ubiquitin ligase function.
Highlights
Reactivation from a latent state is an important feature of infection and disease caused by many herpesviruses
It is likely that there are small ubiquitin-like modifier (SUMO)-dependent and SUMO-independent promoters, which may depend on local chromatin structure and mode of K-Rta recruitment. These results suggest that K-Rta, in addition to being a strong transactivator, has an ability to regulate the local SUMO environment; the latter may contribute to its former functions through disassembly of SUMOinteracting motifs (SIM)-containing co-repressors
In co-transfection experiments, GSK3β present in a latency-associated nuclear antigen (LANA)–GSK-3β complex was unable to phosphorylate a primed peptide substrate. These results were interpreted to suggest that GSK-3β phosphorylation sites on LANA function to increase the affinity of LANA binding to GSK-3β and simultaneously provide a competitive substrate that minimizes potential phosphorylation events on other non-complexed substrates (Fujimuro et al, 2005). These results suggested a model in which LANA sequesters GSK-3β in the nucleus leading to dysregulation of the kinase function in both the cytoplasmic (β-catenin stability) and nuclear compartments (Fujimuro and Hayward, 2003; Fujimuro et al, 2005; Liu et al, 2007)
Summary
Reviewed by: Keiji Ueda, Osaka University Graduate School of Medicine, Japan Masahiro Fujimuro, Kyoto Pharmaceutical University, Japan. KSHV latency can be envisioned as an outcome that is balanced between factors that promote viral gene expression and lytic replication against those that facilitate gene silencing and establish or maintain latency. A large body of work has focused on the activities of the key viral regulatory proteins involved in KSHV latent or lytic states. One area of KSHV molecular virology that remains largely unanswered is the precise role of post-translational modifications on the activities of viral factors that function during latency and reactivation. We will summarize the post-translational modifications associated with three viral factors whose activities contribute to the viral state. The viral proteins discussed are the two major KSHV encoded transcription factors, K-Rta (KSHV replication and transcriptional activator) and K-bZIP (KSHV basic leucine zipper) and the viral latency-associated nuclear antigen (LANA).
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