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The KSHV RNA regulator ORF57: target specificity and its role in the viral life cycle

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Kaposi's sarcoma‐associated herpesvirus (KSHV) encodes ORF57, which enhances the expression of intron‐less KSHV genes on multiple post‐transcriptional levels mainly affecting RNA stability and export to the cytoplasm. Yet, it remains elusive how ORF57 recognizes viral RNAs and discriminates them from cellular messenger RNAs (mRNAs). Although one common binding motif on three separate KSHV RNAs has been described, most other lytic genes lack this sequence element. In this article we will review the sequence requirements for ORF57 to enhance RNA expression and discuss a model how ORF57 achieves specificity for viral RNAs. Finally, the role of ORF57 is integrated into the viral life cycle as a complex interplay with other viral and host factors and with implications for cellular gene expression. WIREs RNA 2016, 7:173–185. doi: 10.1002/wrna.1323 This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA Export and Localization > Nuclear Export/Import RNA Turnover and Surveillance > Regulation of RNA Stability
(a) A KSHV‐infected cell in the latent state is depicted. The circular genome (green circle) is attached to a mitotic chromosome (blue) via the KSHV latent protein LANA (magenta). During latency only a few viral mRNAs (black line with cap (open circle) and poly(A) tail) and miRNAs are transcribed and exported to the cytoplasm. Translation by cellular ribosomes (orange) yield the depicted KSHV proteins. The processed miRNAs search for their cellular targets. (b) In the lytic state genome replication of KSHV occurs in the nucleus of infected cells (green circles). The lytic activation leads a massive viral RNA expression and subsequent translation in the cytoplasm (closed green circles).
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(a) The sequence bias of KSHV lytic genes leads to the decoration of viral RNAs with RBPs, which negatively influence stability (fading orange bar) and export. (b) Sequence optimization in turn yields an RNA with RBPs positively affecting stability and export.
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(a) An intron‐less KSHV gene is depicted blue. The transcribed RNA (black line) is instable (dashed line below) and is degraded via a rapid poly(A)‐dependent decay pathway (yellow pacman). (b) In the presence of ORF57 the TREX complex together with Aly is recruited to the KSHV RNAs. This interaction blocks degradation (red line) and leads to accumulation of ORF57‐bound RNAs.
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(a) The prototypic gene from Figure (a) is portrayed again in a denser version. Transcription and processing leads to the removal of introns (small dashed lines) and the deposition of an exon‐junction complex (EJC, light green circles) on each exon/intron border. 3′ end processing adds a poly(A) tail to the mRNA. (b) Further maturation of mRNP leads to recruitment of the TREX complex (blue circle) and Aly (light pink circle). Aly finally recruit the mRNA export factor TAP/NXT1 (dark blue circle). (c) mRNA export through the nuclear pore is shown. The mRNA enters the nuclear basket (blue lines) 5′→3′ and TAP/NXT1 interacts with the nucleoporins. (d) ORF57 (dark green circle) substitutes for the EJC and binds to viral RNAs (orange) with the help of a cellular factor X (magenta). ORF57 recruits the TREX complex via interaction with Aly as depicted in Figure (b).
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(a) The typical structure of a mammalian gene is shown. Enhancer elements (enh, thick blue line) are up to 100 kb upstream of the core promoter indicated by the dashed line. The ORF (green) is interrupted by introns (dashed lines), which also cover several kilobases. The 3′ UTR is characterized by alternative polyadenylation sites (PAS). (b) A typical KSHV expression unit is illustrated. The promoter (P) is short and contains enhancers. Introns are usually extremely small (>100 nt) and many genes share PAS. The intron‐less ORF is depicted in blue and intron‐containing in orange.
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RNA Export and Localization > Nuclear Export/Import
RNA Turnover and Surveillance > Regulation of RNA Stability
RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes

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