Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF57 protein (also known as mRNA transcript accumulation (Mta)) is a potent posttranscriptional regulator essential for the efficient expression of KSHV lytic genes and productive KSHV replication. ORF57 possesses numerous activities that promote the expression of viral genes, including the three major functions of enhancement of RNA stability, promotion of RNA splicing, and stimulation of protein translation. The multifunctional nature of ORF57 is driven by its ability to interact with an array of cellular cofactors. These interactions are required for the formation of ORF57-containing ribonucleoprotein complexes at specific binding sites in the target transcripts, referred as Mta-responsive elements (MREs). Understanding of the ORF57 protein conformation has led to the identification of two structurally-distinct domains within the ORF57 polypeptide: an unstructured intrinsically disordered N-terminal domain and a structured α-helix-rich C-terminal domain. The distinct structures of the domains serve as the foundation for their unique binding affinities: the N-terminal domain mediates ORF57 interactions with cellular cofactors and target RNAs, and the C-terminal domain mediates ORF57 homodimerization. In addition, each domain has been found to contribute to the stability of ORF57 protein in infected cells by counteracting caspase- and proteasome-mediated degradation pathways. Together, these new findings provide insight into the function and biological properties of ORF57 in the KSHV life cycle and pathogenesis.
Highlights
Productive viral replication depends on the efficient and coordinated expression of viral genes.Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes more than 100 viral genes, which are expressed in a time-dependent manner [1,2,3,4], whereas only few KSHV genes are expressed during the viral latency stage, cascaded expression of all KSHV genes occurs during viral lytic infection.The virus-encoded replication and transcription activator (Rta or ORF50) is essential and sufficient to initiate the KSHV lytic cycle [5,6,7], but completion of the productive KSHV lytic cycle requires expression of the ORF57 protein
Despite its predominantly nuclear localization, a small fraction of ORF57 protein remains in the cytoplasm, where ORF57 associates with the translating ribosomes and cellular factors related to protein translation
Similar to its effect on viral interleukin 6 (vIL-6), ORF57 promotes the expression of human IL-6 by competing with miR-608 for a binding site in the open reading frame (ORF) region that corresponds to the binding region in vIL-6 [79]. These observations provide direct evidence for the functionality of miRNA-binding sites within the coding region, and disclose how ORF57 contributes to high levels of expression of both vIL-6 and hIL-6 during KSHV
Summary
Productive viral replication depends on the efficient and coordinated expression of viral genes. The virus-encoded replication and transcription activator (Rta or ORF50) is essential and sufficient to initiate the KSHV lytic cycle [5,6,7], but completion of the productive KSHV lytic cycle requires expression of the ORF57 protein. Deletion of ORF57 from the virus genome leads to the inefficient expression of viral lytic genes and abortive viral replication [8,9,10]. ORF57 acts on gene expression after ORF50 initiates transcription. This function of ORF57 is responsible for fulfilling the KSHV lytic cycle and viral replication. To KSHV ORF57, all homologues regulate viral gene expression at the posttranscriptional level by interacting with cellular RNA-binding proteins. KSHV ORF57 often deviates from its homologues in several aspects of RNA processing
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