Induction of viral, 7-methyl-guanosine cap-independent translation and oncolysis by mitogen-activated protein kinase-interacting kinase-mediated effects on the serine/arginine-rich protein kinase

Michael C. Brown, Jeffrey D. Bryant, Elena Y. Dobrikova, Mayya Shveygert, Shelton S. Bradrick, Vidyalakshmi Chandramohan, Darell D. Bigner, Matthias Gromeier

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Protein synthesis, the most energy-consuming process in cells, responds to changing physiologic priorities, e.g., upon mitogenor stress-induced adaptations signaled through the mitogen-activated protein kinases (MAPKs). The prevailing status of protein synthesis machinery is a viral pathogenesis factor, particularly for plus-strand RNA viruses, where immediate translation of incoming viral RNAs shapes host-virus interactions. In this study, we unraveled signaling pathways centered on the ERK1/2 and p38α MAPK-interacting kinases MNK1/2 and their role in controlling 7-methyl-guanosine (m7G) "cap"-independent translation at enterovirus type 1 internal ribosomal entry sites (IRESs). Activation of Raf-MEK-ERK1/2 signals induced viral IRES-mediated translation in a manner dependent on MNK1/2. This effect was not due to MNK's known functions as eukaryotic initiation factor (eIF) 4G binding partner or eIF4E(S209) kinase. Rather, MNK catalytic activity enabled viral IRES-mediated translation/host cell cytotoxicity through negative regulation of the Ser/Arg (SR)-rich protein kinase (SRPK). Our investigations suggest that SRPK activity is a major determinant of type 1 IRES competency, host cell cytotoxicity, and viral proliferation in infected cells.

Original languageEnglish (US)
Pages (from-to)13135-13148
Number of pages14
JournalJournal of virology
Volume88
Issue number22
DOIs
StatePublished - Jan 1 2014

    Fingerprint

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this