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Pan RNA is a long non-coding nuclear RNA that is produced by the Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). During the latent phase of the KSHV life cycle, only a few viral genes are expressed and no new viruses are produced. However, during the lytic reactivation phase, a single viral protein, K-Rta (ORF50), activates more than 80 viral genes, including the gene for PAN RNA. PAN RNA is a major target of K-Rta and accumulates to high levels in the nucleus during viral infection. Studies have shown that PAN RNA is important for the activation of KSHV gene expression and virus production, and it may also have a global impact on cellular and viral gene expression programs. In addition to its role in KSHV, PAN RNA motifs have been identified in three bacterial phyla: Chloroflexota, Bacillota, and Pseudomonadota.
| Characteristics | Values |
|---|---|
| Definition | PAN RNA is a long non-coding nuclear RNA (lncRNA) that accumulates to high levels in the nucleus during viral infection |
| Activation | Initiated by a single viral protein, K-Rta (ORF50), which activates more than 80 viral genes |
| Role | PAN RNA facilitates lytic infection and modulates the cellular immune response by interacting with viral and cellular proteins and DNA |
| Structure | PAN RNAs have a simple structure with one or two stem-loops and two bulged adenosines |
| Location | Located in the 5' untranslated regions of genes that encode enzymes involved in pantothenate synthesis |
| Function | PAN RNA suppresses the expression of host genes involved in the antiviral response |
| Transcription | Activated by Rta in Human Herpesvirus 8/Kaposi's Sarcoma-Associated Herpesvirus |
| Abundance | Produced at high levels, with a >1000-fold increase in PAN RNA levels in PAN RNA promoter mutant cells |
| Stabilization | ORF57 stabilizes PAN RNA post-transcriptionally and contributes to increased recruitment of RNA Pol II |
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What You'll Learn
The role of Kaposi's sarcoma-associated herpesvirus (KSHV)
Kaposi's sarcoma-associated herpesvirus (KSHV), also known as Human herpesvirus 8 (HHV-8), is the ninth known human herpesvirus. It is one of seven currently known human cancer viruses or oncoviruses. KSHV is linked to several diseases, including Kaposi's sarcoma, a cancer commonly occurring in AIDS patients, primary effusion lymphoma (PEL), and a subset of multicentric Castleman's disease.
KSHV infection is thought to be lifelong, but individuals with a healthy immune system can keep the virus in check and may never show any symptoms. Kaposi's sarcoma develops when an individual with a KSHV infection becomes immunocompromised due to AIDS, medical treatment, or aging. While there is no known cure for KSHV-associated tumorigenesis, antiviral drugs targeting herpesvirus replication, such as ganciclovir, have been successful in preventing Kaposi's sarcoma development. Chemotherapy with drugs like liposomal anthracyclines or paclitaxel may also be used, especially for invasive disease.
KSHV exhibits a biphasic life cycle consisting of a long-term latent phase and a transient lytic reactivation phase. During the latent phase, only a few viral genes are expressed, and no viral progeny are produced. In contrast, the lytic reactivation phase is characterised by the activation of approximately 80 lytic genes, culminating in the release of new virions. Lytic replication is initiated by the viral protein K-Rta (ORF50), which activates viral genes from multiple resident viral episomes. K-Rta directly targets the PAN promoter, leading to the production of PAN RNA.
Studies have been conducted to understand the role of KSHV in PAN RNA production better. For example, researchers have developed PAN mutants using recombinant bacmids containing the entire KSHV genome. By mutating the K-Rta binding site in the PAN RNA promoter, they observed a significant decrease in PAN RNA expression. Additionally, the activation of the PAN promoter and the transcription of PAN RNA appear crucial for the transactivation of other viral lytic genes.
In summary, KSHV is a human herpesvirus that plays a significant role in the production of PAN RNA. The virus exhibits a biphasic life cycle, with the lytic reactivation phase involving the activation of numerous lytic genes, including PAN RNA, through the viral protein K-Rta. Further research on the interaction between KSHV and PAN RNA may provide insights into the development of therapeutic targets for KSHV-associated diseases.
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PAN RNA's function as a long non-coding nuclear RNA
Polyadenylated nuclear (PAN) RNA is a long non-coding RNA (lncRNA) that is produced during the lytic reactivation phase of the Kaposi's sarcoma-associated herpesvirus (KSHV) life cycle. This virus is also designated human herpesvirus 8 (HHV-8) and has been linked to Kaposi's sarcoma, primary effusion lymphoma (PEL), and a subset of multicentric Castleman's disease.
LncRNAs are defined as transcripts that are longer than 200-500 nucleotides and are not one of the well-characterized RNAs such as siRNAs, mRNAs, miRNAs, or snoRNAs. They occupy a large fraction of the genomes of complex organisms and are known to regulate many aspects of cell differentiation, development, and other physiological processes. LncRNAs are also implicated in various diseases, including cancer, where they are thought to play a crucial role in regulating cellular processes.
PAN RNA is a major target of the viral protein K-Rta (ORF50), which activates the expression of more than 80 viral genes during the lytic reactivation phase of KSHV. The PAN promoter is a direct target of K-Rta, and mutations in the K-Rta binding site in the PAN RNA promoter result in significantly reduced PAN RNA expression.
The function of PAN RNA as a lncRNA is not yet fully understood, but it is known to accumulate to exceedingly high levels in the nucleus during viral infection. The activation of the PAN promoter and active transcription of PAN RNA are important for the transactivation of other viral lytic genes. PAN RNA may also contribute to the increased recruitment of RNA Pol II through its interaction with K-Rta and/or nascent RNA molecules.
In summary, PAN RNA is a lncRNA that plays a significant role in the life cycle of KSHV and is a major target of the viral protein K-Rta. The function of PAN RNA as a lncRNA is an active area of research, and its high expression during viral infection suggests that it may have important regulatory roles in the virus's life cycle.
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The biphasic life cycle of KSHV
Kaposi's sarcoma-associated herpesvirus (KSHV) exhibits a biphasic life cycle consisting of a life-long latent phase and a transient lytic reactivation phase.
During the latent phase, the viral episome is tethered to the host chromosome and replicates once during every cell division. This is facilitated by the latency-associated nuclear antigen (LANA), a predominant multifunctional nuclear protein expressed during latency, which plays a central role in episome tethering, replication, and perpetual segregation of the episomes during cell division. Latency is the default life cycle for KSHV following host cell infections, and only a few viral genes are expressed during this phase.
The lytic reactivation phase is initiated by a single viral protein, K-Rta (ORF50), which activates more than 80 viral genes from multiple resident viral episomes. This phase involves the consecutive expression of most viral genes, resulting in the production and release of new infectious virion particles. Lytic replication is short, and the virus does not kill the resident host to promote its survival and reproduction.
KSHV has evolved strategies to evade the host immune response, enabling the virus to establish a successful lifelong infection. The virus can utilise host proteins, such as heparan sulfate, integrin, and ephrin A2, as receptors to facilitate attachment to the cell membrane. The biphasic nature of the KSHV life cycle, with its distinct latent and lytic phases, is crucial for the long-term persistence of the virus in the host and the pathogenesis of KSHV-associated diseases.
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The role of the PAN promoter during viral reactivation
Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), has been linked to Kaposi's sarcoma and other AIDS-related malignancies. KSHV has a biphasic life cycle, with a latent phase and a transient lytic reactivation phase. During the lytic reactivation phase, a single viral protein, K-Rta (ORF50), initiates lytic replication by activating more than 80 viral genes. One of K-Rta's major targets is PAN RNA, a long non-coding nuclear RNA that accumulates to high levels in the nucleus during viral reactivation.
The PAN promoter plays a crucial role during viral reactivation. K-Rta directly binds to the PAN RNA promoter and activates PAN RNA expression. This binding and activation of the PAN promoter are essential for the transactivation of many other viral lytic genes. The PAN locus serves as a hub for the sequestration of the cellular transcriptional machinery, including RNA Pol II, proximal to viral episomes. This sequestration facilitates high levels of viral transcription during lytic replication.
Interactions between K-Rta, ORF57, RNA Pol II, and nascent PAN RNA contribute to the trapping of RNA Pol II at the PAN promoter, further enhancing PAN RNA production. ORF57 also stabilizes PAN RNA post-transcriptionally and may increase the recruitment of RNA Pol II through interactions with K-Rta and/or nascent RNA molecules. The activation of the PAN promoter and PAN RNA transcription are critical for the optimal expression of lytic genes needed for the entire lytic program.
Additionally, CCAAT/enhancer-binding protein-alpha (C/EBPα) plays a role during the early stages of KSHV lytic cycle reactivation. C/EBPα, in cooperation with the KSHV replication and transcription activator (RTA), stimulates the viral RTA, MTA, and PAN promoters. The RTA protein is necessary for reactivating the virus from latency, and its nuclear localization is directly linked to viral promoter transactivation.
In summary, the PAN promoter is a key player in viral reactivation, as it is directly targeted by K-Rta to activate PAN RNA expression. This activation has downstream effects on the expression of other viral lytic genes, contributing to the overall lytic program of KSHV. The PAN promoter and PAN RNA thus play essential roles in the viral life cycle and pathogenesis of KSHV-associated diseases.
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PAN RNA's ability to regulate gene expression
PAN RNA (polyadenylated nuclear RNA) is a long non-coding RNA (lncRNA) that is produced by the Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). This virus is linked to Kaposi's sarcoma, primary effusion lymphoma (PEL), and a subset of multicentric Castleman's disease.
During the KSHV infection, PAN RNA accumulates to very high levels in the nucleus. PAN RNA is transcribed from a K-Rta responsive promoter, which has a high affinity for K-Rta, resulting in increased transcription levels. The secondary structure of PAN RNA, specifically the ENE region, also contributes to its abundance by protecting the poly(A) tail from degradation.
PAN RNA has been shown to play a crucial role in regulating gene expression, both cellular and viral. It interacts with chromatin-modifying complexes and works in cis and trans to control gene expression. One of the key mechanisms by which PAN RNA regulates gene expression is by mediating chromatin modification, specifically targeting the KSHV repressed genome. Depletion of PAN RNA in infected cells has been found to impair KSHV late gene expression and reduce the amount of infectious virus.
Furthermore, PAN RNA's ability to regulate gene expression is closely tied to its interaction with other proteins and factors. For instance, PAN RNA interacts with histones H1 and H2A, mitochondrial and cellular single-stranded binding proteins, interferon regulatory factor 4 (IRF4), and KSHV ORF59. It also interferes with the ability of IRF4/PU.1 to activate the interleukin-4 (IL-4) promoter. Additionally, PAN RNA's role in gene expression is influenced by the ORF57 protein, which stabilizes PAN RNA post-transcriptionally and contributes to the recruitment of RNA Pol II through interaction with K-Rta and/or nascent RNA molecules.
The study of PAN RNA and its role in gene expression has led to advancements in understanding cancer and virus-induced diseases, providing potential diagnostic and therapeutic targets. PAN RNA-Seq analysis has been instrumental in revealing the existence of 5' and 3' end small RNAs, which can be used to annotate nuclear non-coding and mitochondrial genes, leading to the discovery of new genes and biological functions.
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Frequently asked questions
PAN RNA (polyadenylated nuclear RNA) is a long non-coding RNA that accumulates to high levels in the nucleus during viral infection. It is a major target of the viral protein K-Rta (ORF50), which activates viral genes.
PAN RNA is produced by the Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). KSHV exhibits a biphasic life cycle with a latent phase and a lytic reactivation phase. During the lytic phase, K-Rta activates the PAN promoter, leading to the production of PAN RNA.
PAN RNA is a multifunctional regulatory transcript that controls gene expression by mediating chromatin modification. It has been linked to the disregulation of immune response genes and the formation of the inflammasome, suggesting a global impact on cellular and viral gene expression programs.
