Abstract
Nuclear mRNA export is a highly complex and regulated process in cells. Cellular transcripts must undergo successful maturation processes, including splicing, 5'-, and 3'-end processing, which are essential for assembly of an export competent ribonucleoprotein particle. Many viruses replicate in the nucleus of the host cell and require cellular mRNA export factors to efficiently export viral transcripts. However, some viral mRNAs undergo aberrant mRNA processing, thus prompting the viruses to express their own specific mRNA export proteins to facilitate efficient export of viral transcripts and allowing translation in the cytoplasm. This review will focus on the Kaposi’s sarcoma-associated herpesvirus ORF57 protein, a multifunctional protein involved in all stages of viral mRNA processing and that is essential for virus replication. Using the example of ORF57, we will describe cellular bulk mRNA export pathways and highlight their distinct features, before exploring how the virus has evolved to exploit these mechanisms.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8), belongs to the lymphotropic (γ) herpesvirus subfamily [1] and is the causative agent of three human cancers: multicentricCastleman’s disease (MCD) [2], primary effusion lymphoma (PEL) [3], and Kaposi’s sarcoma (KS) [4].While PEL and multicentricCastleman’s disease (MCD) are both rare B-cell lymphoproliferative disorders, KS, an aggressive tumour of Viruses 2013, 5 endothelial origin, has become one of the most common cancers in many sub-Saharan African countries where individuals are co-infected with HIV and KSHV [5]
These findings suggest that while the mechanism of interacting with the human cellular export machinery may vary between herpesviruses, the requirement of recruiting transcription-coupled export (TREX) to viral mRNAs via ORF57 and its homologues appears to be evolutionarily conserved
Since the discovery of KSHV in 1994 [4] there has been a large body of work investigating the latent-lytic switch and the immediate-early proteins that regulate the lytic cycle
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8), belongs to the lymphotropic (γ) herpesvirus subfamily [1] and is the causative agent of three human cancers: multicentric. The virus establishes latency in the majority of these infected cells, during which the genome is maintained as a large circular episome in the nucleus of the cell and only a very small subset of viral genes are expressed, resulting in no infectious virions being released. Under certain stimuli, such as hypoxia [12], lytic replication is reactivated in a small proportion of cells leading to expression of more than 80 transcripts, release of infectious virions and cell lysis. Lytic replication allows dissemination of the virus from the initial reservoir of infected cells to endothelial cells where tumours may develop. To highlight the role of ORF57 the concept of mammalian mRNA export will first be explored
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