Article

Kaposi's sarcoma-associated herpesvirus K-bZIP represses gene transcription via SUMO modification.

Department of Biological Chemistry, University of California--Davis (UC Davis), School of Medicine, Sacramento, 95817, USA.
Journal of Virology (Impact Factor: 4.65). 09/2005; 79(15):9912-25. DOI: 10.1128/JVI.79.15.9912-9925.2005
Source: PubMed

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus implicated in AIDS-related neoplasms. Previously, we demonstrated that the early lytic gene product K-bZIP is a transcriptional repressor that affects a subset of viral gene transcriptions mediated by the viral transactivator K-Rta (Y. Izumiya et al. J. Virol. 77:1441-1451, 2003). Sumoylation has emerged as an important posttranslational modification that affects the location and function of cellular and viral proteins and also plays a significant role in transcriptional repression along with Ubc9, the E2 SUMO conjugation enzyme. Here, we provide evidence that K-bZIP is sumoylated at the lysine 158 residue and associates with Ubc9 both in a cell-free system and in virus-infected BCBL-1 cells. Reporter assays showed that the expression of SUMO-specific protease 1 attenuated the transcriptional repression activity of K-bZIP. The expression of a K-bZIPK158R mutant, which was no longer sumoylated, exhibited the reduced transcriptional repression activity. This indicates that sumoylation plays an important part in the transcriptional repression activity of K-bZIP. Finally, chromatin immunoprecipitation experiments demonstrated that K-bZIP interacts with and recruits Ubc9 to specific KSHV promoters. Thus, our data indicate that K-bZIP is a SUMO adaptor, which recruits Ubc9 to specific viral target promoters, thereby exerting its transcriptional repression activity.

0 Bookmarks
 · 
88 Views
  • Source
    [Show abstract] [Hide abstract]
    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.
    12/2014; 6(4):1905-1924. DOI:10.3390/cancers6041905
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Kaposi's sarcoma-associated herpesvirus (KSHV/human herpesvirus 8) is a γ-herpesvirus linked to Kaposi's sarcoma (KS) and two lymphoproliferative disorders, primary effusion lymphoma (PEL or body-cavity B-lymphoma [BCBL]) and a subset of Multicentric Castleman's Disease. During lytic growth, pervasive viral transcription generating a variety of transcripts with uncertain protein-coding potential has been described on a genome-wide scale in β- and γ-herpesviruses. One class of such RNAs is called long non-coding RNAs (lncRNAs). KSHV encodes a viral lncRNA known as polyadenylated nuclear RNA (PAN RNA), a copious early gene product. PAN RNA has been implicated in KSHV gene expression, replication, and immune modulation. PAN RNA expression is required for optimal expression of the entire KSHV lytic gene expression program. Latent KSHV episomes are coated with viral latency-associated nuclear antigen (LANA). LANA rapidly dissociates from episomes during reactivation. Here we review recent studies suggesting that PAN RNA may function as a viral lncRNA, including a role in the facilitation of LANA-episomal dissociation during lytic replication.
    Viruses 11/2014; 6(11):4165-4177. DOI:10.3390/v6114165 · 3.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Kaposi's sarcoma-associated herpesvirus (KSHV) primarily persists as a latent episome in infected cells. During latent infection, only a limited number of viral genes are expressed that help to maintain the viral episome and prevent lytic reactivation. The latent KSHV genome persists as a highly ordered chromatin structure with bivalent chromatin marks at the promoter-regulatory region of the major immediate-early gene promoter. Various stimuli can induce chromatin modifications to an active euchromatic epigenetic mark, leading to the expression of genes required for the transition from the latent to the lytic phase of KSHV life cycle. Enhanced replication and transcription activator (RTA) gene expression triggers a cascade of events, resulting in the modulation of various cellular pathways to support viral DNA synthesis. RTA also binds to the origin of lytic DNA replication to recruit viral, as well as cellular, proteins for the initiation of the lytic DNA replication of KSHV. In this review we will discuss some of the pivotal genetic and epigenetic factors that control KSHV reactivation from the transcriptionally restricted latent program.
    Viruses 01/2015; 7(1):116-153. DOI:10.3390/v7010116 · 3.28 Impact Factor

Full-text (2 Sources)

Download
6 Downloads
Available from
Nov 28, 2014