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Profiling the RNA-Binding Proteome of KSHV-Infected Cells Uncovers a Viral Strategy for Hijacking Host Signaling via RNA-Dependent Interactions.

ABSTRACT: Viruses encode RNA-binding proteins (RBPs) to manipulate host processes and promote infection. However, due to limited genomic space, many viral proteins are multifunctional and may engage RNA through non-canonical domains, making their identification difficult using traditional sequence-based approaches. Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of many AIDS-associated cancers. Here, leveraging an unbiased proteomic approach we identified all RBPs in KSHV-infected primary effusion lymphoma (PEL) cells, uncovering 7 previously unrecognized KSHV-encoded RBPs. Among these is viral Interferon Regulatory Factor 1 (vIRF1), which we found is both necessary and sufficient to activate oncogenic RAS/MAPK signaling through an RNA-dependent interaction with host G3BP proteins. Importantly, a KSHV vIRF1 mutant lacking the ability to bind RNA exhibits a B cell-specific replication defect, highlighting the essential role of RNA interactions in viral gene regulation and pathogenesis. These findings reveal a novel strategy by which KSHV hijacks RNA-mediated signaling to support its lifecycle.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308077 | GEO | 2026/08/07

REPOSITORIES: GEO

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Project description:Enhancers play indispensable roles in cell proliferation and survival through spatiotemporally regulating gene transcription. In addition, active enhancers and super-enhancers often produce noncoding enhancer RNAs (eRNAs) that precisely control RNA polymerase II activity. Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human oncogenic gamma-2 herpesvirus that causes Kaposi’s sarcoma and lymphoproliferative diseases of B-cell origin such as primary effusion lymphoma (PEL). It is well characterized that KSHV utilizes host epigenetic and nuclear machineries to control the switch between two life cycles, latency and lytic replication. However, how KSHV impacts the host epigenome at different stages of viral life cycle is not well understood. Using the analysis of global run-on sequencing (GRO-seq) and chromatin-immunoprecipitation sequencing (ChIP-seq), we profiled the dynamics of host transcriptional regulatory elements during latency and lytic replication of KSHV-infected PEL cells. This study showed that a number of critical host genes for KSHV latency, including MYC proto-oncogene, were under the control of super-enhancers and eRNAs that were globally repressed upon viral reactivation. A combination of circular chromosome conformation capture combined with sequencing (4C-seq), GRO-seq and ChIP-seq indicated that the eRNA-expressing super-enhance regions were located at downstream of the MYC gene in KSHV-infected PELs. Treatment of an epigenetic drug to block enhancer function or shRNA-mediated depletion of the eRNA expression significantly reduced MYC mRNA expression in KSHV-infected PELs. Finally, while cellular IRF4 acted upon the eRNAs and super-enhancers for MYC expression during latency, the KSHV viral IRF4 repressed cellular IRF4 expression upon reactivation, decreasing MYC expression and thereby, facilitating lytic replication. Taken together, these data suggest that KSHV acts as an epigenetic driver that modifies host epigenomic status by effectively regulating enhancer function upon reactivation.

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Profiling the RNA-Binding Proteome of KSHV-Infected Cells Uncovers a Viral Strategy for Hijacking Host Signaling via RNA-Dependent Interactions.

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