Characterisation of the interactions between the KSHV ORF57 protein and the human TREX complex

作者: Sophie Schumann

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摘要: Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human oncovirus associated with multiple malignancies, including sarcoma (KS). Like all herpesviruses, KSHV can establish either latent or lytic infection in host cells. During latency the virus remains dormant state, limited gene expression. After reactivation, enters life cycle, characterised by production of infectious virions and subsequent dissemination from its reservoir. Importantly, replication critical for KS tumourigenesis. KSHV replicates nucleus cell requires cellular mRNA export factors to efficiently viral mRNAs nucleus, allowing their translation cytoplasm. But while mammalian linked splicing, majority genome encodes intronless mRNAs, prompting circumvent this step. therefore expresses ORF57, multifunctional protein essential replication. ORF57 recruits members transcription/export (hTREX) complex form an competent ribonucleoprotein particle (vRNP), facilitating efficient nuclear mRNAs. This study presents novel mechanism specific disruption vRNP inhibition Results suggest ATP-cycle dependent remodelling hTREX, which affects ability interact vRNP. Specifically, inhibiting ATP hydrolysis hTREX component ATPase UAP56 prevents recruiting complex, key components endogenous remain able interact. Following finding, was targeted small molecule inhibitors, using structure-based drug design approach, prevent thereby formation. Strikingly, hit compound identified shown disrupt formation vRNP, expression virion production, within therapeutic window, where no cytotoxicity observed. Bearing mind conserved export, finally series compounds that are both HSV-1

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