A viral kinase mimics S6 kinase to enhance cell proliferation

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 fra...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 113; no. 28; pp. 7876 - 7881
Main Authors Bhatt, Aadra Prashant, Wong, Jason P., Weinberg, Marc S., Host, Kurtis M., Giffin, Louise C., Buijnink, Joshua, van Dijk, Evert, Izumiya, Yoshihiro, Kung, Hsing-jien, Temple, Brenda R. S., Damania, Blossom
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 12.07.2016
Subjects
Biological Sciences
Computer Simulation
HEK293 Cells
Herpesvirus 8, Human - enzymology
Human Umbilical Vein Endothelial Cells
Humans
Models, Molecular
Ribosomal Protein S6 Kinases, 70-kDa - chemistry
Ribosomal Protein S6 Kinases, 70-kDa - metabolism
Substrate Specificity
Viral Proteins - chemistry
Viral Proteins - metabolism
ORF36
S6K
KSHV
viral protein kinase
cell signaling
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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.
AbstractList 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.
Viruses usurp the host cell machinery to replicate, disseminate, and propagate themselves. Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes a viral protein kinase (vPK) also known as ORF36. Using in silico modeling and biochemistry, we report that vPK/ORF36 displays limited homology to cellular S6 kinase B1 (S6KB1). Both kinases share overlapping substrates and can phosphorylate S6. However, unlike S6KB1, vPK augments S6 phosphorylation under conditions where mammalian target of rapamycin (mTOR) is inhibited. vPK modulates cellular proliferation and protein synthesis, augments anchorage independence, and enhances angiogenesis. Depletion of vPK/ORF36 during lytic replication inhibits the production of infectious virions, thereby underscoring the importance of this kinase during the KSHV life cycle. Our collective observations suggest that vPK may function as a constitutively active mimic of S6KB1. 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.
Author Weinberg, Marc S.
Giffin, Louise C.
Izumiya, Yoshihiro
Temple, Brenda R. S.
Kung, Hsing-jien
Damania, Blossom
Bhatt, Aadra Prashant
Host, Kurtis M.
Buijnink, Joshua
Wong, Jason P.
van Dijk, Evert
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Keywords ORF36
S6K
KSHV
viral protein kinase
cell signaling
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Author contributions: A.P.B. and B.D. designed research; A.P.B., J.P.W., M.S.W., K.M.H., L.C.G., J.B., and E.v.D. performed research; Y.I. and H.-j.K. contributed new reagents/analytic tools; A.P.B., J.P.W., J.B., E.v.D., B.R.S.T., and B.D. analyzed data; and A.P.B. and B.D. wrote the paper.
Edited by Elliott Kieff, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, and approved May 17, 2016 (received for review January 15, 2016)
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Snippet Viruses depend upon the host cell for manufacturing components of progeny virions. To mitigate the inextricable dependence on host cell protein synthesis,...
Viruses usurp the host cell machinery to replicate, disseminate, and propagate themselves. Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes a viral...
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SubjectTerms Biological Sciences
Computer Simulation
HEK293 Cells
Herpesvirus 8, Human - enzymology
Human Umbilical Vein Endothelial Cells
Humans
Models, Molecular
Ribosomal Protein S6 Kinases, 70-kDa - chemistry
Ribosomal Protein S6 Kinases, 70-kDa - metabolism
Substrate Specificity
Viral Proteins - chemistry
Viral Proteins - metabolism
Title A viral kinase mimics S6 kinase to enhance cell proliferation
URI https://www.jstor.org/stable/26470811
https://www.ncbi.nlm.nih.gov/pubmed/27342859
https://search.proquest.com/docview/1804203578
https://pubmed.ncbi.nlm.nih.gov/PMC4948314
Volume 113
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