Kaposi's Sarcoma-Associated Herpesvirus-Encoded Protein Kinase and Its Interaction with K-bZIP

Department of Internal Medicine, University of California, Davis, Davis, California, United States
Journal of Virology (Impact Factor: 4.44). 03/2007; 81(3):1072-82. DOI: 10.1128/JVI.01473-06
Source: PubMed


The oncogenic herpesvirus, Kaposi's sarcoma-associated herpesvirus, also identified as human herpesvirus 8, contains genes producing proteins that control transcription and influence cell signaling. Open reading frame 36 (ORF36) of this virus encodes a serine/threonine protein kinase, which is designated the viral protein kinase (vPK). Our recent efforts to elucidate the role of vPK in the viral life cycle have focused on identifying viral protein substrates and determining the effects of vPK-mediated phosphorylation on specific steps in viral replication. The vPK gene was transcribed into 4.2-kb and 3.6-kb mRNAs during the early and late phases of viral reactivation. vPK is colocalized with viral DNA replication/transcription compartments as marked by a polymerase processivity factor, and K-bZIP, a protein known to bind the viral DNA replication origin (Ori-Lyt) and to regulate viral transcription. The vPK physically associated with and strongly phosphorylated K-bZIP at threonine 111, a site also recognized by the cyclin-dependent kinase Cdk2. Both K-bZIP and vPK were corecruited to viral promoters targeted by K-bZIP as well as to the Ori-Lyt region. Phosphorylation of K-bZIP by vPK had a negative impact on K-bZIP transcription repression activity. The extent of posttranslational modification of K-bZIP by sumoylation, a process that influences its repression function, was decreased by vPK phosphorylation at threonine 111. Our data thus identify a new role of vPK as a modulator of viral transcription.

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Available from: Albert Van Geelen
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    • "K-bZIP is a nuclear transcription factor that is a strong repressor when sumoylated at lysine 158 [76]. Phosphorylation at threonine 111 prevents sumoylation and converts K-bZIP to a strong transcriptional activator [77]. Chang et al. showed that K-bZIP has a SIM motif at residues 73–77 that binds SUMO2/3 but not SUMO1 [73]. "
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    ABSTRACT: Many viral proteins have been shown to be sumoylated with corresponding regulatory effects on their protein function, indicating that this host cell modification process is widely exploited by viral pathogens to control viral activity. In addition to using sumoylation to regulate their own proteins, several viral pathogens have been shown to modulate overall host sumoylation levels. Given the large number of cellular targets for SUMO addition and the breadth of critical cellular processes that are regulated via sumoylation, viral modulation of overall sumoylation presumably alters the cellular environment to ensure that it is favorable for viral reproduction and/or persistence. Like some viruses, certain bacterial plant pathogens also target the sumoylation system, usually decreasing sumoylation to disrupt host anti-pathogen responses. The recent demonstration that Listeria monocytogenes also disrupts host sumoylation, and that this is required for efficient infection, extends the plant pathogen observations to a human pathogen and suggests that pathogen modulation of host sumoylation may be more widespread than previously appreciated. This review will focus on recent aspects of how pathogens modulate the host sumoylation system and how this benefits the pathogen.
    Full-text · Article · Apr 2012
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    • "K-bZIP directly associates with K-Rta in KSHV infected cells and represses K-Rta-mediated transactivation at a subset of KSHV promoters. This activity of K-bZIP is subject to post-translational modulation via phosphorylation (Izumiya et al., 2007) and sumoylation (Izumiya et al., 2005). As detailed below, K-bZIP repression activity on K-Rta-mediated transactivation is regulated in an opposing manner by these two post-translational modifications. "
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    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.
    Preview · Article · Feb 2012 · Frontiers in Microbiology
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    • "Amongst the conserved gene products are the orthologous serine/threonine protein kinases, UL13, UL97, BGLF4 and ORF36, encoded by herpes simplex type 1 (HSV1), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV) and Kaposi's sarcoma associated herpesvirus (KSHV) respectively (Gershburg and Pagano, 2008). These kinases are structurally similar to the cellular kinase cdk2 (Romaker et al., 2006) and are recognized to phosphorylate a number of cyclin dependent kinase cellular targets including pRb (Hume et al., 2008), condensin (Lee et al., 2007), stathmin (Chen et al., 2010), lamin A/C (Hamirally et al., 2009; Lee et al., 2008; Meng et al., 2010), elongation factor 1 delta (Kato et al., 2001; Kawaguchi and Kato, 2003; Kawaguchi et al., 2003), MCM4 (Kudoh et al., 2006) and p27/KIP1 (Iwahori et al., 2009) as well as viral targets including KSHV bZIP (RAP) (Izumiya et al., 2007), EBV EBNA1 and virion proteins (Zhu et al., 2009) and HCMV UL69 (Rechter et al., 2009). Deletion of the protein kinases or inhibition of their activity has been shown to impair virus replication of HCMV and EBV in cultured cells (Gershburg et al., 2007; Prichard et al., 1999; Wolf et al., 2001) and to reduce the titer of HSV1 and murine gamma herpesvirus 68 (γ-HV68) in infected mice (Shibaki et al., 2001; Tarakanova et al., 2007). "
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    ABSTRACT: Herpesviruses, which are major human pathogens, establish life-long persistent infections. Although the α, β, and γ herpesviruses infect different tissues and cause distinct diseases, they each encode a conserved serine/threonine kinase that is critical for virus replication and spread. The extent of substrate conservation and the key common cell-signaling pathways targeted by these kinases are unknown. Using a human protein microarray high-throughput approach, we identify shared substrates of the conserved kinases from herpes simplex virus, human cytomegalovirus, Epstein-Barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus. DNA damage response (DDR) proteins were statistically enriched, and the histone acetyltransferase TIP60, an upstream regulator of the DDR pathway, was required for efficient herpesvirus replication. During EBV replication, TIP60 activation by the BGLF4 kinase triggers EBV-induced DDR and also mediates induction of viral lytic gene expression. Identification of key cellular targets of the conserved herpesvirus kinases will facilitate the development of broadly effective antiviral strategies.
    Full-text · Article · Oct 2011 · Cell host & microbe
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