Virus-like vesicles of Kaposi’s Sarcoma-Associated Herpesvirus activate lytic replication through triggering differentiation signaling
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA356918PRJNA356917PRJNA356883
ORGANISM(S): Human gammaherpesvirus 8 Homo sapiens
PROVIDER: GSE91386 | GEO | 2017/05/03
SECONDARY ACCESSION(S): PRJNA356883
REPOSITORIES: GEO
Similar Datasets
Project description:Virus-like vesicles (VLVs) are membrane derived cellular vesicles that resemble native envelope viruses in organization and conformation, but lack viral capsid and/or genome. During productive virus infection, both infectious virions and non-infectious VLVs are produced and released into the extracellular space. VLVs have been shown to play a role in intercellular communication and in facilitating virus infection. The study of VLVs in the context of gammaherpesvirus infection has been largely restricted due to the technical difficulty of separating VLVs and virions. Here we report a strategy for using a KSHV mutant deficient in capsid assembly to isolate VLVs during infection. Using Mass Spectrometry analysis, we identified that VLVs contain viral glycoproteins required for cellular entry, and tegument proteins involved in regulating lytic replication. Functional analysis showed that VLVs could activate the RTA promoter, the lytic switch for KSHV, and further induce KSHV lytic gene expression from latency. We used RNA sequencing to do a genome-wide analysis of cellular responses triggered by VLVs, and revealed that PRDM1, a master regulator in cell differentiation, was up-regulated. Our data shows that VLVs play an important role in promoting KSHV lytic replication by inducing PRDM1 expression which activates the RTA promoter. Our study significantly extends our current understanding of VLVs.
2017-05-03 | GSE91385 | GEO
Project description:Virus-like vesicles (VLVs) are membrane derived cellular vesicles that resemble native envelope viruses in organization and conformation, but lack viral capsid and/or genome. During productive virus infection, both infectious virions and non-infectious VLVs are produced and released into the extracellular space. VLVs have been shown to play a role in intercellular communication and in facilitating virus infection. The study of VLVs in the context of gammaherpesvirus infection has been largely restricted due to the technical difficulty of separating VLVs and virions. Here we report a strategy for using a KSHV mutant deficient in capsid assembly to isolate VLVs during infection. Using Mass Spectrometry analysis, we identified that VLVs contain viral glycoproteins required for cellular entry, and tegument proteins involved in regulating lytic replication. Functional analysis showed that VLVs could activate the RTA promoter, the lytic switch for KSHV, and further induce KSHV lytic gene expression from latency. We used RNA sequencing to do a genome-wide analysis of cellular responses triggered by VLVs, and revealed that PRDM1, a master regulator in cell differentiation, was up-regulated. Our data shows that VLVs play an important role in promoting KSHV lytic replication by inducing PRDM1 expression which activates the RTA promoter. Our study significantly extends our current understanding of VLVs.
2017-05-03 | GSE91384 | GEO
Project description:Virus-like vesicles (VLVs) are membrane-enclosed vesicles that resemble native enveloped viruses in organization but lack the viral capsid and genome. During the productive infection of tumor-associated gammaherpesviruses, both virions and VLVs are produced and are released into the extracellular space. However, studies of gammaherpesvirus-associated VLVs have been largely restricted by the technical difficulty of separating VLVs from mature virions. Here we report a strategy of selectively isolating VLVs by using a Kaposi's sarcoma-associated herpesvirus (KSHV) mutant that is defective in small capsid protein and is unable to produce mature virions. Using mass spectrometry analysis, we found that VLVs contained viral glycoproteins required for cellular entry, as well as tegument proteins involved in regulating lytic replication, but lacked capsid proteins. Functional analysis showed that VLVs induced the expression of the viral lytic activator RTA, initiating KSHV lytic gene expression. Furthermore, employing RNA sequencing, we performed a genomewide analysis of cellular responses triggered by VLVs and found that PRDM1, a master regulator in cell differentiation, was significantly upregulated. In the context of KSHV replication, we demonstrated that VLV-induced upregulation of PRDM1 was necessary and sufficient to reactivate KSHV by activating its RTA promoter. In sum, our study systematically examined the composition of VLVs and demonstrated their biological roles in manipulating host cell responses and facilitating KSHV lytic replication.IMPORTANCE Cells lytically infected with tumor-associated herpesviruses produce a high proportion of virus-like vesicles (VLVs). The composition and function of VLVs have not been well defined, largely due to the inability to efficiently isolate VLVs that are free of virions. Using a cell system capable of establishing latent KSHV infection and robust reactivation, we successfully isolated VLVs from a KSHV mutant defective in the small capsid protein. We quantitatively analyzed proteins and microRNAs in VLVs and characterized the roles of VLVs in manipulating host cells and facilitating viral infection. More importantly, we demonstrated that by upregulating PRDM1 expression, VLVs triggered differentiation signaling in targeted cells and facilitated viral lytic infection via activation of the RTA promoter. Our study not only demonstrates a new strategy for isolating VLVs but also shows the important roles of KSHV-associated VLVs in intercellular communication and the viral life cycle.
| S-EPMC5651724 | biostudies-literature
Project description:Virus-like vesicles of Kaposi’s Sarcoma-Associated Herpesvirus activate lytic replication through triggering differentiation signaling
| PRJNA356883 | ENA
Project description:Virus-like vesicles of Kaposi’s Sarcoma-Associated Herpesvirus activate lytic replication through triggering differentiation signaling (mRNA)
| PRJNA356918 | ENA
Project description:Virus-like vesicles of Kaposi’s Sarcoma-Associated Herpesvirus activate lytic replication through triggering differentiation signaling (microRNA)
| PRJNA356917 | ENA
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 | PXD032367 | Pride
Project description:To investigate the regulation of ER stress-related gene expression by KSHV-ORF45 during lytic replication, we performed RNA-sequencing analysis of iSLK-BAC16 vs. iSLK-STOP45 cells under lytic induction for 72h. When the differentially expressed genes were filtered and analyzed, we found that ER stress-related gene expression was much low in iSLK-STOP45 cells compared with iSLK-BAC16 cells, indicating that ORF45 expression is required for induction of ER stress.To further reveal the signal transduction of LAMP3 in KSHV lytic replication, RNA-sequencing analysis was performed to identify the differentially expressed genes (DEGs) in normal vs. LAMP3-silenced cells under lytic replication. A total of 35372 raw read targets were obtained and all DEG clusters were filtered and analyzed by KEGG pathway enrichment analysis. Eleven pathway were significantly enriched over 10 fold in LAMP3-depleted cells compared with control cells, including PI3K-Akt signaling pathway.Given that Akt and ERK activation play the important roles in KSHV lytic replication, we conclude that LAMP3 might promote Akt and ERK activation and then consequently facilitate KSHV lytic replication.
2022-11-09 | GSE192724 | GEO
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:The majority of AIDS-associated primary effusion lymphomas (PEL) are latently infected with both Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). PELs harboring two viruses have higher oncogenic potential, suggesting functional interactions between EBV and KSHV. The KSHV replication and transcription activator (K-RTA) is necessary and sufficient for induction of KSHV lytic replication. EBV latent membrane protein 1 (LMP-1) is essential for EBV transformation and establishment of latency in vitro. We show EBV inhibits chemically induced KSHV lytic replication, in part because of a regulatory loop in which K-RTA induces EBV LMP-1 and LMP-1 in turn inhibits K-RTA expression and furthermore the lytic gene expression of KSHV. Suppression of LMP-1 expression in dually infected PEL cells enhances the expression of K-RTA and lytic replication of KSHV upon chemical induction. Because LMP-1 is known to inhibit EBV lytic replication, KSHV-mediated induction of LMP-1 would potentiate EBV latency. Moreover, KSHV infection of EBV latency cells induces LMP-1, and K-RTA is involved in the induction. Both LMP-1 and K-RTA are expressed during primary infection by EBV of KSHV latency cells. Our findings provide evidence that an interaction between EBV and KSHV at molecular levels promotes the maintenance and possibly establishment of viral latency, which may contribute to pathogenesis of PELs.
| S-EPMC1900272 | biostudies-literature