Mechanism of sustained activation of ribosomal S6 kinase (RSK) and ERK by kaposi sarcoma-associated herpesvirus ORF45: multiprotein complexes retain active phosphorylated ERK AND RSK and protect them from dephosphorylation.
As obligate intracellular parasites, viruses exploit diverse cellular signaling machineries, including the mitogen-activated protein-kinase pathway, during their infections. We have demonstrated previously that the open reading frame 45 (ORF45) of Kaposi sarcoma-associated herpesvirus interacts with p90 ribosomal S6 kinases (RSKs) and strongly stimulates their kinase activities ( Kuang, E., Tang, Q., Maul, G. G., and Zhu, F. (2008) J. Virol. 82, 1838-1850 ). Here, we define the mechanism by which ORF45 activates RSKs. We demonstrated that binding of ORF45 to RSK increases the association of extracellular signal-regulated kinase (ERK) with RSK, such that ORF45, RSK, and ERK formed high molecular mass protein complexes. We further demonstrated that the complexes shielded active pERK and pRSK from dephosphorylation. As a result, the complex-associated RSK and ERK were activated and sustained at high levels. Finally, we provide evidence that this mechanism contributes to the sustained activation of ERK and RSK in Kaposi sarcoma-associated herpesvirus lytic replication.
Kuang
Ersheng
E
Department of Biological Science, Florida State University, Tallahassee, Florida 32306-4370.
Wu
Fayi
F
Department of Biological Science, Florida State University, Tallahassee, Florida 32306-4370.
Zhu
Fanxiu
F
Department of Biological Science, Florida State University, Tallahassee, Florida 32306-4370. Electronic address: fzhu@bio.fsu.edu.
D002460:Cell Line; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*
D017874:Immediate-Early Proteins; D046912:Multiprotein Complexes; C456286:ORF45 protein, Kaposi's sarcoma-associated herpesvirus; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D020929:Mitogen-Activated Protein Kinase Kinases