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Kaposi’s Sarcoma-associated herpesvirus fine-tunes the temporal expression of its genes manipulating a specific host RNA quality control pathway

ABSTRACT: Kaposi’s Sarcoma-associated herpesvirus (KSHV) transcripts are subject to degradation by at least two host-mediated nuclear RNA decay pathways, PABPN1 and PAPα/γ-mediated RNA decay (PPD) and an ARS2-dependent decay pathway. KSHV expresses the multifunctional protein ORF57, which increases viral transcripts stability by protecting them preferentially from ARS2-dependent decay. However, a subset of viral transcripts succumb to PPD even in the presence of ORF57, but the role of PPD during KSHV infection is not completely understood. We inactivated both decay pathways using siRNA and monitored their contribution to viral gene expression in the presence of ORF57 by RNA-Seq at 24 hours post induction (hpi). Inactivation of PPD, but not ARS2-mediated decay, results in aberrant accumulation of late transcripts, which are typically expressed at 48 hpi. PPD exerts its functions post-transcriptionally as the upregulation of late genes is independent of viral transactivation factors needed for their expression. Remarkably, at their proper time of expression, PPD inactivation has no effect on late transcripts. We further show that PPD evasion by late transcripts requires the host factor NRDE2. In conclusion, our studies show that KSHV uses PPD to fine-tune the temporal expression of its genes by preventing their premature accumulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144747 | GEO | 2020/04/28

REPOSITORIES: GEO

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Project description:The Kaposi's sarcoma associated herpesvirus (KSHV) is an oncogenic virus that causes Kaposi's sarcoma, primary effusion lymphoma (PEL), and some forms of multicentric Castleman's disease. The KSHV ORF57 protein is a conserved posttranscriptional regulator of gene expression that is essential for virus replication. ORF57 is multifunctional, but most of its activities are directly linked to its ability to bind RNA. We globally identified virus and host RNAs bound by ORF57 during lytic reactivation in PEL cells using high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). As expected, ORF57-bound RNA fragments mapped throughout the KSHV genome, including the known ORF57 ligand PAN RNA. In agreement with previously published ChIP results, we observed that ORF57 bound RNAs near the oriLyt regions of the genome. Examination of the host RNA fragments revealed that a subset of the ORF57-bound RNAs was derived from transcript 5´ ends. The position of these 5´-bound fragments correlated closely with the 5´-most exonintron junction of the pre-mRNA. We selected four candidates (BTG1, EGR1, ZFP36, and TNFSF9) and analyzed their pre-mRNA and mRNA levels during lytic phase. Analysis of both steady-state and newly made RNAs revealed that these candidate ORF57-bound pre-mRNAs persisted for longer periods of time throughout infection than control RNAs, consistent with a role for ORF57 in pre-mRNA metabolism. In addition, exogenous expression of ORF57 was sufficient to increase the pre-mRNA levels and, in one case, the mRNA levels of the putative ORF57 targets. These results demonstrate that ORF57 interacts with specific host pre-mRNAs during lytic reactivation and alters their processing, likely by stabilizing pre-mRNAs. These data suggest that ORF57 is involved in modulating host gene expression in addition to KSHV gene expression during lytic reactivation. HITS-CLIP was performed on TREx BCBL-Rta cells 20 hpi using antibodies against ORF57. Three biological replicates were performed.

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Kaposi’s Sarcoma-associated herpesvirus fine-tunes the temporal expression of its genes manipulating a specific host RNA quality control pathway

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