A viral kinase mimics S6 kinase to enhance cell proliferation

Abstract

Viruses depend upon the host cell for manufacturing components of progeny virions. To mitigate the inextricable dependence on host cell protein synthesis, viruses can modulate protein synthesis through a variety of mechanisms. We report that the viral protein kinase (vPK) encoded by open reading frame 36 (ORF36) of Kaposi's sarcoma-associated herpesvirus (KSHV) enhances protein synthesis by mimicking the function of the cellular protein S6 kinase (S6KB1). Similar to S6KB1, vPK phosphorylates the ribosomal S6 protein and up-regulates global protein synthesis. vPK also augments cellular proliferation and anchorage-independent growth. Furthermore, we report that both vPK and S6KB1 phosphorylate the enzyme 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 2 (PFKFB2) and that both kinases promote endothelial capillary tubule formation.cell signaling | viral protein kinase | S6K | KSHV | ORF36

Human herpesvirus–encoded kinase induces B cell lymphomas in vivo

“…We reported that vPK resembles and mimics the activity of the cellular ribosomal protein S6 kinase β-1 (S6KB1) (25). S6KB1 is downstream in the PI3K pathway and is phosphorylated by mTOR, a serine/threonine kinase that is part of several complexes within the PI3K pathway (33).…”

“…S6 is a component of the 40S ribosome subunit, and its phosphorylation is important for the ribosomal biogenesis transcriptional program (51). vPK phosphorylates S6, and increased phosphorylated S6 correlates with increased global protein synthesis, tubule formation, and anchorage-independent growth in cell culture (25). These data suggest that one potential mechanism by which vPK promotes tumorigenesis may be by its phosphorylation of S6.…”

“…The KSHV ORF36 construct was previously described (25) and was cloned into the backbone pBS.Ub.hGH, a plasmid previously modified from pBluescript to include a Ub and a stabilization sequence (hGH). The plasmid was linearized with restriction enzymes PvuI-HF (high fidelity) and SapI from New England BioLabs.…”

“…Our lab has previously shown that vPK is an S6KB1 mimic (25). S6KB1 is downstream in the PI3K/mTOR pathway and is phosphorylated by mTOR.…”

“…Although S6KB1 and vPK share some of the same substrates, such as S6, vPK expression also appears to promote the phosphorylation of proteins that are not substrates of S6KB1, such as eIF4E (25). Eukaryotic initiation factor 4E binds to the mRNA 5′ cap structure, thereby promoting recruitment of mRNA to the ribosome.…”