Open AccessInhibition of viral protein translation by indomethacin in vesicular stomatitis virus infection: role of e IF 2α kinase PKR
Author(s) -
Amici Carla,
La Frazia Simone,
Brunelli Claudia,
Balsamo Mirna,
Angelini Mara,
Santoro M. Gabriella
Publication year - 2015
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/cmi.12446
Subject(s) - protein kinase r , vesicular stomatitis virus , biology , virology , protein kinase a , virus , translation (biology) , kinase , mitogen activated protein kinase kinase , microbiology and biotechnology , messenger rna , biochemistry , gene
Summary Indomethacin, a cyclooxygenase‐1 and ‐2 inhibitor widely used in the clinic for its potent anti‐inflammatory/analgesic properties, possesses antiviral activity against several viral pathogens; however, the mechanism of antiviral action remains elusive. We have recently shown that indomethacin activates the double‐stranded RNA ( dsRNA )‐dependent protein kinase R ( PKR ) in human colon cancer cells. Because of the important role of PKR in the cellular defence response against viral infection, herein we investigated the effect of indomethacin on PKR activity during infection with the prototype rhabdovirus vesicular stomatitis virus. Indomethacin was found to activate PKR in an interferon‐ and dsRNA‐independent manner, causing rapid (< 5 min) phosphorylation of eukaryotic initiation factor‐2 α‐subunit (e IF 2α). These events resulted in shutting off viral protein translation and blocking viral replication ( IC 50 = 2 μ M ) while protecting host cells from virus‐induced damage. Indomethacin did not affect e IF 2α kinases PKR ‐like endoplasmic reticulum‐resident protein kinase ( PERK ) and general control non‐derepressible‐2 ( GCN 2) kinase, and was unable to trigger e IF 2α phosphorylation in the presence of PKR inhibitor 2‐aminopurine. In addition, small‐interfering RNA ‐mediated PKR gene silencing dampened the antiviral effect in indomethacin‐treated cells. The results identify PKR as a critical target for the antiviral activity of indomethacin and indicate that e IF 2α phosphorylation could be a key element in the broad spectrum antiviral activity of the drug.