Antiviral effect of the mammalian translation initiation factor 2alpha kinase GCN2 against RNA viruses.
In mammals, four different protein kinases, heme-regulated inhibitor, double-stranded RNA-dependent protein kinase (PKR), general control non-derepressible-2 (GCN2) and PKR-like endoplasmic reticulum kinase, regulate protein synthesis in response to environmental stresses by phosphorylating the alpha-subunit of the initiation factor 2 (eIF2alpha). We now report that mammalian GCN2 is specifically activated in vitro upon binding of two nonadjacent regions of the Sindbis virus (SV) genomic RNA to its histidyl-tRNA synthetase-related domain. Moreover, endogenous GCN2 is activated in cells upon SV infection. Strikingly, fibroblasts derived from GCN2-/- mice possess an increased permissiveness to SV or vesicular stomatitis virus infection. We further show that mice lacking GCN2 are extremely susceptible to intranasal SV infection, demonstrating high virus titers in the brain compared to similarly infected control animals. The overexpression of wild-type GCN2, but not the catalytically inactive GCN2-K618R variant, in NIH 3T3 cells impaired the replication of a number of RNA viruses. We determined that GCN2 inhibits SV replication by blocking early viral translation of genomic SV RNA. These findings point to a hitherto unrecognized role of GCN2 as an early mediator in the cellular response to RNA viruses.
Berlanga
Juan J
JJ
Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Facultad de Ciencias, Cantoblanco, Universidad Autónoma de Madrid, Madrid, Spain.
Ventoso
Iván
I
Harding
Heather P
HP
Deng
Jing
J
Ron
David
D
Sonenberg
Nahum
N
Carrasco
Luis
L
de Haro
César
C
D018354:Alphavirus Infections / Q000201:enzymology / Q000276:immunology / Q000821:virology; D000818:Animals; D001921:Brain / Q000821:virology; D002460:Cell Line; D004789:Enzyme Activation; D016679:Genome, Viral; D006801:Humans; D051379:Mice; D009154:Mutation; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D012845:Sindbis Virus / Q000235:genetics / Q000502:physiology*; D014721:Vesicular stomatitis Indiana virus / Q000502:physiology; D014779:Virus Replication
D012367:RNA, Viral; D011494:Protein Kinases; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases