IL-6 Evades KSHV-Mediated Hyperadenylation repression via CRM1-Dependent Nuclear Export.
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ABSTRACT:
PROVIDER: PRJNA1269618 | ENA |
REPOSITORIES: ENA
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Project description:RNA turnover is critical for regulating gene expression and cellular homeostasis, with nuclear export representing a key step in mRNA fate. During lytic reactivation of Kaposi’s Sarcoma-associated Herpesvirus (KSHV), widespread host mRNA decay is mediated by the viral endonuclease SOX, which depletes cytoplasmic transcripts and induces secondary nuclear RNA processing defects. One such defect includes transcript hyperadenylation, which typically promotes nuclear retention and decay. However, a subset of host mRNAs escapes both SOX-mediated degradation and nuclear retention, raising questions about their export mechanisms and stability. Here, we investigate the impact of KSHV infection on mRNA poly(A) tail length and nuclear export dynamics using high-throughput poly(A)-sequencing of nuclear and cytoplasmic RNA fractions from KSHV-positive cells. Our data confirm a global increase in poly(A) tail length during KSHV lytic infection, consistent with transcript hyperadenylation. Nevertheless, we identified a group of hyperadenylated transcripts that remain cytoplasmically localized, suggesting active evasion of nuclear retention. Notably, we focused on interleukin-6 (IL-6), a known SOX escapee, which retains cytoplasmic expression during lytic infection despite acquiring a longer poly(A) tail. Using G/I tailing and sPAT assays, we confirmed IL-6 hyperadenylation and demonstrate that its export is CRM1-dependent rather than through the canonical NXF1-NXT1 pathway, which is suppressed during host shutoff. Pharmacological inhibition of CRM1 impairs IL-6 nuclear export and reduces steady-state RNA levels, implicating CRM1 export in the stabilization of this transcript. Our findings reveal a previously unrecognized mechanism by which select host mRNAs, including IL-6, bypass KSHV-imposed nuclear export blocks and escape nuclear decay, thereby preserving their function during viral infection. This study highlights viral manipulation of RNA processing and export pathways as a critical determinant of transcript fate and identifies CRM1 as a key mediator of selective host transcript preservation during KSHV lytic reactivation.
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Project description:Nuclear pore proteins (Nups) physically interact with hundreds of chromosomal sites, impacting transcription. In yeast, transcription factors mediate interactions between Nups and enhancers and promoters. To define the molecular basis of this mechanism, we exploited a separation-of-function mutation in the Gcn4 transcription factor that blocks its interaction with the nuclear pore complex (NPC). This mutation reduces the interaction of Gcn4 with the highly conserved nuclear export factor Crm1/Xpo1. Crm1 and Nups co-occupy enhancers and Crm1 inhibition blocks interaction of the nuclear pore protein Nup2 with the genome. In vivo, Crm1 interacts stably with the NPC. In vitro, Crm1 binds both Gcn4 and Nup2 directly. Importantly, the interaction between Crm1 and Gcn4 requires neither Ran-GTP nor the nuclear export sequence binding site. Finally, Crm1 and Ran-GTP stimulate DNA binding by Gcn4, suggesting that allosteric coupling between Crm1-Ran-GTP binding and DNA binding facilitates docking of transcription factor-bound enhancers at the NPC.
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Project description:We used ChIP-seq to examine the genome-wide binding of Nup98-HoxA9 and Crm1 in ES cells. Our analysis revealed that Nup98-HoxA9 is highly and preferentially targeted to specific chromatin sites, particularly near Hox cluster regions where the export factor Crm1 is originally prebound. chromatin immunoprecipitation
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Project description:Nuclear pore proteins (Nups) physically interact with hundreds of chromosomal sites, impacting transcription. In yeast, transcription factors mediate interactions between Nups and enhancers and promoters. To define the molecular basis of this mechanism, we exploited a separation-of-function mutation in the Gcn4 transcription factor that blocks its interaction with the nuclear pore complex (NPC). This mutation reduces the interaction of Gcn4 with the highly conserved nuclear export factor Crm1/Xpo1. Crm1 and Nups co-occupy enhancers and Crm1 inhibition blocks interaction of the nuclear pore protein Nup2 with the genome. In vivo, Crm1 interacts stably with the NPC. In vitro, Crm1 binds both Gcn4 and Nup2 directly. Importantly, the interaction between Crm1 and Gcn4 requires neither Ran-GTP nor the nuclear export sequence binding site. Finally, Crm1 and Ran-GTP stimulate DNA binding by Gcn4, suggesting that allosteric coupling between Crm1-Ran-GTP binding and DNA binding facilitates docking of transcription factor-bound enhancers at the NPC.
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Project description:CRM1 mediates one of the major nuclear export pathways with the broadest range of cargoes. So far, more than 100 structurally and functionally diverse CRM1 cargoes have been described. We employed affinity purification mass spectrometry for in depth characterization of CRM1 "exportome" in three model systems and we identified surprisingly large numbers, namely >700 export substrates from the yeast S. cerevisiae, ≈ 1000 from Xenopus oocytes and >1050 from human cells.I. Futher, we quantified the partitioning of ≈9600 proteoforms between nucleus and cytoplasm of Xenopus oocytes.
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Project description:Nuclear pore proteins (Nups) physically interact with hundreds of chromosomal sites, impacting transcription. In yeast, transcription factors mediate interactions between Nups and enhancers and promoters. To define the molecular basis of this mechanism, we exploited a separation-of-function mutation in the Gcn4 transcription factor that blocks its interaction with the nuclear pore complex (NPC). This mutation reduces the interaction of Gcn4 with the highly conserved nuclear export factor Crm1/Xpo1. Crm1 and Nups co-occupy enhancers and Crm1 inhibition blocks interaction of the nuclear pore protein Nup2 with the genome. In vivo, Crm1 interacts stably with the NPC. In vitro, Crm1 binds both Gcn4 and Nup2 directly. Importantly, the interaction between Crm1 and Gcn4 requires neither Ran-GTP nor the nuclear export sequence binding site. Finally, Crm1 and Ran-GTP stimulate DNA binding by Gcn4, suggesting that allosteric coupling between Crm1-Ran-GTP binding and DNA binding facilitates docking of transcription factor-bound enhancers at the NPC.
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Project description:We used ChIP-seq to examine the genome-wide binding of Nup98-HoxA9 and Crm1 in ES cells. Our analysis revealed that Nup98-HoxA9 is highly and preferentially targeted to specific chromatin sites, particularly near Hox cluster regions where the export factor Crm1 is originally prebound.
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Project description:Nuclear pore proteins (Nups) physically interact with hundreds of chromosomal sites, impacting transcription. In yeast, transcription factors mediate interactions between Nups and enhancers and promoters. To define the molecular basis of this mechanism, we exploited a separation-of-function mutation in the Gcn4 transcription factor that blocks its interaction with the nuclear pore complex (NPC). This mutation reduces the interaction of Gcn4 with the highly conserved nuclear export factor Crm1/Xpo1. Crm1 and Nups co-occupy enhancers and Crm1 inhibition blocks interaction of the nuclear pore protein Nup2 with the genome. In vivo, Crm1 interacts stably with the NPC. In vitro, Crm1 binds both Gcn4 and Nup2 directly. Importantly, the interaction between Crm1 and Gcn4 requires neither Ran-GTP nor the nuclear export sequence binding site. Finally, Crm1 and Ran-GTP stimulate DNA binding by Gcn4, suggesting that allosteric coupling between Crm1-Ran-GTP binding and DNA binding facilitates docking of transcription factor-bound enhancers at the NPC.
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