title: Phosphorylation of eukaryotic translation initiation factor 4B (EIF4B) by open reading frame 45/p90 ribosomal S6 kinase (ORF45/RSK) signaling axis facilitates protein translation during Kaposi sarcoma-associated herpesvirus (KSHV) lytic replication.
abstract: Open reading frame 45 (ORF45) of Kaposi sarcoma-associated herpesvirus (KSHV) causes sustained activation of p90 ribosomal S6 kinase (RSK), which is crucial for KSHV lytic replication, but the exact functional roles remain to be determined. To characterize the biological consequence of persistent RSK activation by ORF45, we screened known cellular substrates of RSK. We found that ORF45 induced phosphorylation of eukaryotic translation initiation factor 4B (eIF4B), increased its assembly into translation initiation complex, and subsequently facilitated protein translation. The ORF45/RSK-mediated eIF4B phosphorylation was distinguishable from that caused by the canonical AKT/mammalian target of rapamycin/ribosomal S6 kinase and MEK/ERK/RSK pathways because it was resistant to both rapamycin (an mammalian target of rapamycin inhibitor) and U1026 (an MEK inhibitor). The rapamycin and U1026 doubly insensitive eIF4B phosphorylation was induced during KSHV reactivation but was abolished if either ORF45 or RSK1/2 were ablated by siRNA, a pattern that is correlated with reduced lytic gene expression as we observed previously. Ectopic expression of eIF4B but not its phosphorylation-deficient mutant form increased KSHV lytic gene expression and production of progeny viruses. Together, these results indicated that ORF45/RSK axis-induced eIF4B phosphorylation is involved in translational regulation and is required for optimal KSHV lytic replication.
authors: Department of Biological Science, The Florida State University, Tallahassee, Florida 32306-4370.
authors: Ersheng
authors: E
authors: Kuang
authors: Department of Biological Science, The Florida State University, Tallahassee, Florida 32306-4370.
authors: Bishi
authors: B
authors: Fu
authors: Department of Biological Science, The Florida State University, Tallahassee, Florida 32306-4370.
authors: Qiming
authors: Q
authors: Liang
authors: Novartis Institutes for Biomedical Research, Emeryville, California 94608-2916.
authors: Jinjong
authors: J
authors: Myoung
authors: Department of Biological Science, The Florida State University, Tallahassee, Florida 32306-4370. Electronic address: fzhu@bio.fsu.edu.
authors: Fanxiu
authors: F
authors: Zhu
mesh_terms: D045744:Cell Line, Tumor; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
chemical_list: D039642:Eukaryotic Initiation Factors; D017874:Immediate-Early Proteins; D007166:Immunosuppressive Agents; C456286:ORF45 protein, Kaposi's sarcoma-associated herpesvirus; C031799:eIF-4B; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D058570:TOR Serine-Threonine Kinases; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D020123:Sirolimus