Post‐transcriptional gene regulation by gamma herpesviruses

Swaminathan, Sankar

doi:10.1002/jcb.20465

Cited by 40 publications

(36 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These include well-characterized HSV-1 ICP27 (28), human cytomegalovirus virus (HCMV) UL69 (29), Epstein-Barr virus (EBV) EB2 (or EB-SM) (30), and herpesvirus saimiri (HVS) ORF57 (31). While all homologues in the family share many common activities, they diverge with regard to specific functions and target specificities.…”

mentioning

confidence: 99%

Stability of Structured Kaposi's Sarcoma-Associated Herpesvirus ORF57 Protein Is Regulated by Protein Phosphorylation and Homodimerization

Majerčiak

Pripuzova

Chan

et al. 2015

J Virol

View full text Add to dashboard Cite

Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 plays an essential role in KSHV lytic infection by promoting viral gene expression at the posttranscriptional level. Using bioinformatic and biochemical approaches, we determined that ORF57 contains two structurally and functionally distinct domains: a disordered nonstructural N-terminal domain (amino acids [aa] 1 to 152) and a structured ␣-helix-rich C-terminal domain (aa 153 to 455). The N-terminal domain mediates ORF57 interaction with several RNA-protein complexes essential for ORF57 to function. The N-terminal phosphorylation by cellular casein kinase II (CKII) at S21, T32, and S43, and other cellular kinases at S95 and S97 residues in proximity of the caspase-7 cleavage site, 30-DETD-33, inhibits caspase-7 digestion of ORF57. The structured C-terminal domain mediates homodimerization of ORF57, and the critical region for this function was mapped carefully to ␣-helices 7 to 9. Introduction of point mutations into ␣-helix 7 at ORF57 aa 280 to 299, a region highly conserved among ORF57 homologues from other herpesviruses, inhibited ORF57 homodimerization and led to proteasome-mediated degradation of ORF57 protein. Thus, homodimerization of ORF57 via its C terminus prevents ORF57 from degrading and allows two structure-free N termini of the dimerized ORF57 to work coordinately for host factor interactions, leading to productive KSHV lytic infection and pathogenesis. IMPORTANCEKSHV is a human oncogenic virus linked to the development of several malignancies. KSHV-mediated oncogenesis requires both latent and lytic infection. The KSHV ORF57 protein is essential for KSHV lytic replication, as it regulates the expression of viral lytic genes at the posttranscriptional level. This report provides evidence that the structural conformation of the ORF57 protein plays a critical role in regulation of ORF57 stability. Phosphorylation by CKII on the identified serine/threonine residues at the N-terminal unstructured domain of ORF57 prevents its digestion by caspase-7. The C-terminal domain of ORF57, which is rich in ␣-helices, contributes to homodimerization of ORF57 to prevent proteasome-mediated protein degradation. Elucidation of the ORF57 structure not only enables us to better understand ORF57 stability and functions but also provides an important tool for us to modulate ORF57's activity with the aim to inhibit KSHV lytic replication. K aposi's sarcoma-associated herpesvirus (KSHV) ORF57 (also known as Mta) is expressed early in the KSHV lytic cycle and is required for the efficient expression of a subset of viral genes, including KSHV PAN, ORF59, K8, viral interleukin-6 (vIL-6), ORF47, and others (1-7). A KSHV genome lacking ORF57 expression is associated with a defective lytic cycle incapable of producing infectious virions (8, 9).KSHV ORF57 functions as a posttranscriptional regulator of viral gene expression by affecting RNA stability (PAN, ORF59, and ORF47), splicing (ORF50 and K8), polyadenylation (ORF59), and translation (vIL-6) (1, 2, 4-7, 10) but ...

show abstract

mentioning

confidence: 99%

Stability of Structured Kaposi's Sarcoma-Associated Herpesvirus ORF57 Protein Is Regulated by Protein Phosphorylation and Homodimerization

Majerčiak

Pripuzova

Chan

et al. 2015

J Virol

View full text Add to dashboard Cite

show abstract

“…Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a multifunctional regulator of gene expression called ORF57 (Mta) that has been implicated in transcriptional control, splicing regu-lation, translation, and mRNA export (2,10,48,73). ORF57 interacts directly with both REF/Aly and viral mRNAs which, in some cases, increases the export efficiency of the mRNA (1,47,49,54).…”

mentioning

confidence: 99%

Viral Factors Reveal a Role for REF/Aly in Nuclear RNA Stability

Stubbs

Hunter

Hoover

et al. 2012

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…Although ORF57 orthologues have different nomenclatures among different viruses (MTA or ORF57 for KSHV, SM for Epstein-Barr virus, ICP27 for herpes simplex virus, etc. ), they all function to enhance the expression of delayed-early and late genes of the virus (27,30,40). The deletion or interruption of ORF57 orthologues is deleterious for infectious virion production, demonstrating their critical role for virus replication (15,25).…”

mentioning

confidence: 99%

Rhesus Monkey Rhadinovirus ORF57 Induces gH and gL Glycoprotein Expression through Posttranscriptional Accumulation of Target mRNAs

Shin

Desrosiers

2011

J Virol

View full text Add to dashboard Cite

Open reading frame 57 (ORF57) of gamma-2 herpesviruses is a key regulator of viral gene expression. It has been reported to enhance the expression of viral genes by transcriptional, posttranscriptional, or translational activation mechanisms. Previously we have shown that the expression of gH and gL of rhesus monkey rhadinovirus (RRV), a close relative of the human Kaposi's sarcoma-associated herpesvirus (KSHV), could be dramatically rescued by codon optimization as well as by ORF57 coexpression (J. P. Bilello, J. S. Morgan, and R. C. Desrosiers, J. Virol. 82:7231-7237, 2008). We show here that ORF57 coexpression and codon optimization had similar effects, except that the rescue of expression by codon optimization was temporally delayed relative to that of ORF57 coexpression. The transfection of gL mRNA directly into cells with or without ORF57 coexpression and with or without codon optimization recapitulated the effects of these modes of induction on transfected DNA. These findings suggested an important role for the enhancement of mRNA stability and/or the translation of mRNA for these very different modes of induced expression. This conclusion was confirmed by several different measures of gH and gL mRNA stability and accumulation with or without ORF57 coexpression and with or without codon optimization. Our results indicate that RRV gH and gL expression is severely limited by the stability of the mRNA and that ORF57 coexpression and codon optimization independently induce gH and gL expression principally by allowing accumulation and translation of these mRNAs.

show abstract

Post‐transcriptional gene regulation by gamma herpesviruses

Cited by 40 publications

References 65 publications

Stability of Structured Kaposi's Sarcoma-Associated Herpesvirus ORF57 Protein Is Regulated by Protein Phosphorylation and Homodimerization

Stability of Structured Kaposi's Sarcoma-Associated Herpesvirus ORF57 Protein Is Regulated by Protein Phosphorylation and Homodimerization

Viral Factors Reveal a Role for REF/Aly in Nuclear RNA Stability

Rhesus Monkey Rhadinovirus ORF57 Induces gH and gL Glycoprotein Expression through Posttranscriptional Accumulation of Target mRNAs

Contact Info

Product

Resources

About