An integrative approach identifies direct targets of the late viral transcription complex and an expanded promoter recognition motif in Kaposi’s sarcoma-associated herpesvirus
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ABSTRACT:
ORGANISM(S): Human gammaherpesvirus 8 Homo sapiens
PROVIDER: GSE126603 | GEO | 2019/02/16
REPOSITORIES: GEO
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Project description:The structural proteins of DNA viruses are generally encoded by late genes, whose expression relies on recruitment of the host transcriptional machinery only after the onset of viral genome replication. β and γ-herpesviruses encode a unique six-member viral pre-initiation complex (vPIC) for this purpose, although how the vPIC directs specific activation of late genes remains largely unknown. The specificity underlying late transcription is particularly notable given that late gene promoters are unusually small, with a modified TATA-box being the only recognizable element. Here, we explored the basis for this specificity using an integrative approach to evaluate vPIC-dependent gene expression combined with promoter occupancy during Kaposi's sarcoma-associated herpesvirus (KSHV) infection. This approach distinguished the direct and indirect targets of the vPIC, ultimately revealing a novel promoter motif critical for KSHV vPIC binding. Additionally, we found that the KSHV vPIC component ORF24 is required for efficient viral DNA replication and identified a ORF24 binding element in the origin of replication that is necessary for late gene promoter activation. Together, these results identify an elusive element that contributes to vPIC specificity and suggest novel links between KSHV DNA replication and late transcription.
| S-EPMC6541308 | biostudies-literature
Project description:An integrative approach identifies direct targets of the late viral transcription complex and an expanded promoter recognition motif in Kaposi’s sarcoma-associated herpesvirus
| PRJNA522740 | ENA
Project description:Objective Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s sarcoma (KS) and Primary effusion lymphoma (PEL), which are usually seen in immunocompromised patients while lack of effective therapeutic options. Interleukin1 (IL1) family is a major mediator for inflammation response and has functional role in both innate and adaptive immunity. In contrast to the well-studied IL1 molecules, the activation and functional role of IL1 receptor/co-receptor and other related ligands, such as the IL1 receptor accessory protein (IL1RAP), in KSHV pathogenesis and tumorigenesis remain almost unknown. Methods In the current study, a series of KSHV negative and positive primary or tumor cells, as well as AIDS-KS tumor samples from cohort HIV+ patients were used to compare and determine the activation status of IL1 signaling molecules, and their functional roles in KSHV pathogenesis. Results We reported the high activation of multiple IL1 signaling molecules, including IL1, IL36, IL1R1, IL1RAP and IRAKs, during KSHV latent and lytic stages, as well as in clinical samples from patients with KSHV-related malignancies. Directly targeting these molecules especially IL1R1 and IL1RAP significantly impaired the survival and growth of KSHV+ tumor cells, as well as their colony formation on 3-D culture. Conclusion Our data indicate the importance of IL1 signaling molecules in KSHV pathogenesis and tumorigenesis, which may represent attractive therapeutic targets against these virus-associated diseases.
| S-EPMC9705745 | biostudies-literature
Project description:Lytic replication is essential for persistent infection of Kaposi’s sarcoma-associated herpesvirus (KSHV) and the pathogenesis of related diseases, and many cellular pathways are hijacked by KSHV proteins to initiate and control the lytic replication of this virus. However, the machinery involved in KSHV lytic replication from the early to the late phases remains largely undetermined. We previously revealed that KSHV ORF45 plays important roles in late transcription and translation. In the present study, we reveal that the Forkhead box proteins FoxK1 and FoxK2 are ORF45-binding proteins and are essential for KSHV lytic gene expression and virion production and that depletion of FoxK1 or FoxK2 significantly suppresses the expression of many late viral genes. FoxK1 and FoxK2 directly bind to the promoters of several late viral genes, ORF45 augments the promoter binding and transcriptional activity of FoxK1 and FoxK2, and then FoxK1 or FoxK2 cooperates with ORF45 to promote late viral gene expression. Our findings suggest that ORF45 interacts with FoxK1 and FoxK2 and promotes their occupancy on a cluster of late viral promoters and their subsequent transcriptional activity; consequently FoxK1 and FoxK2 promote late gene expression to facilitate KSHV lytic replication.
2024-08-05 | GSE273577 | GEO
Project description: Not available
| EMPIAR-12541 | biostudies-other
Project description:Human umbilical vein endothelial cells (HUVECs) expressing vPK (HUVEC-vPK) have a survival advantage over control HUVEC under conditions of extrinsic- and intrinsic-mediated apoptosis.
2023-09-16 | GSE241970 | GEO
Project description:Chromatin Immuno-precipitaion sequencing was performed using H3-Ac, H3K4Me3, H3K9Me3, H3K27Me3, LANA, RTA and DNA Polymerase 1 alpha antibodies to investigate its enrichment on Kaposi's sarcoma associated herpesvirus (KSHV) genome in BC3 cells under normoxic or hypoxic conditions
2022-08-15 | GSE202670 | GEO
Project description:The RNA recognition motif (or RRM) is a ubiquitous RNA-binding module present in approximately 2% of the proteins encoded in the human genome. This work characterizes an expanded RRM, which is present in the Drosophila Bruno protein, and targets regulatory elements in the oskar mRNA through which Bruno controls translation. In this Bruno RRM, the deletion of 40 amino acids prior to the N-terminus of the canonical RRM resulted in a significantly decreased affinity of the protein for its RNA target. NMR spectroscopy showed that the expanded Bruno RRM contains the familiar RRM fold of four antiparallel beta-strands and two alpha-helices, preceded by a 10-residue loop that contacts helix alpha(1) and strand beta(2); additional amino acids at the N-terminus of the domain are relatively flexible in solution. NMR results also showed that a truncated form of the Bruno RRM, lacking the flexible N-terminal amino acids, forms a stable and complete canonical RRM, so that the loss of RNA binding activity cannot be attributed to disruption of the RRM fold. This expanded Bruno RRM provides a new example of the features that are important for RNA recognition by an RRM-containing protein.
| S-EPMC4301712 | biostudies-literature
Project description:Historically, ribosomes have been viewed as unchanged homogeneous macromolecular machines with no intrinsic regulatory capacity for mRNA translation. However, an emerging concept is that heterogeneity of ribosomal composition exists, which can exert a regulatory function or specificity in translational control. This is supported by recent discoveries identifying compositionally distinct ‘specialised ribosomes’ that actively regulate mRNA translation. Viruses lack their own translational machinery and impose a high translational demand on the host cell during replication. Here we explore the possibility that Kaposi’s sarcoma-associated herpesvirus (KSHV) can manipulate host ribosome biogenesis during infection to produce specialised ribosomes which preferentially translate viral transcripts. Quantitative proteomic analysis has identified changes in the stoichiometry and composition of precursor ribosomal complexes during the switch from latent to lytic KSHV replication. Intriguingly, we demonstrate the enhanced association of ribosomal biogenesis factors BUD23 and NOC4L, and a previously uncharacterised KSHV lytic protein, ORF11, with small ribosomal subunit precursor complexes during lytic KSHV infection. Notably, BUD23 depletion resulted in significantly reduced viral gene expression and progression through the lytic cascade, culminating in a dramatic reduction of infectious virion production. Importantly, ribosome profiling demonstrated that BUD23 is essential for the reduced association of ribosomes with KSHV uORFs in late lytic genes, required for the efficient translation of the main open reading frame. Together our results provide new mechanistic insights into KSHV-mediated manipulation of cellular ribosome composition inducing a population of specialised ribosomes to facilitate efficient translation of viral mRNAs.
2022-12-21 | PXD032318 | Pride
Project description:Pseudouridylation is a prevalent RNA modification shown to occur in tRNAs, rRNAs, snoRNAs and most recently mRNAs and ncRNAs. Emerging evidence suggests that this dynamic RNA modification is implicated in altering gene expression by regulating RNA stability, modulating translation elongation and modifying amino acid substitution rates. However, the role of pseudouridylation in infection is poorly understood. Here we demonstrate that Kaposi’s sarcoma-associated herpesvirus (KSHV) manipulates the pseudouriylation pathway to enhance replication. We show the pseudouridine synthases (PUS), PUS1 and PUS7 are essential for efficient KSHV lytic replication, supported by the redistribution of PUS7 to viral replication and transcription complexes. Here we present a comprehensive analysis of KSHV RNA pseudouridylation revealing hundreds of modified RNAs at single-nucleotide resolution. Notably, we further demonstrate that pseudouridylation of the KSHV-encoded polyadenylated nuclear RNA (PAN) plays a significant role in the stability of PAN RNA and in the association of the KSHV ORF57 protein. Our findings reveal a novel and essential role of pseudouridine modification in the KSHV replication cycle.
2025-11-05 | GSE217688 | GEO