Phosphorylation of the NFAR proteins by the dsRNA-dependent protein kinase PKR constitutes a novel mechanism of translational regulation and cellular defense.
Here, we describe a new mechanism of host defense that involves the nuclear factors associated with dsRNA (NFAR1 [90 kDa] and NFAR2 [110 kDa]), which constitute part of the shuttling ribonuclear protein (RNP) complex. Activation of the dsRNA-activated protein kinase PKR by viral RNA enabled phosphorylation of NFAR1 and NFAR2 on Thr 188 and Thr 315, an event found to be evolutionarily conserved in Xenopus. Phosphorylated NFAR1 and NFAR2 became dissociated from nuclear factor 45 (NF45), which was requisite for NFAR reshuttling, causing the NFARs to be retained on ribosomes, associate with viral transcripts, and impede viral replication. Cre-loxP animals with depletion of the NFARs in the thymus were exquisitely sensitive to the cytoplasmic replicating virus VSV (vesicular stomatitis virus). Thus, the NFARs constitute a novel, conserved mechanism of host defense used by the cell to detect and impede aberrant translation events.
Department of Medicine, University of Miami School of Medicine, Florida 33136, USA.
Ai
A
Harashima
Toumy
T
Guettouche
Glen N
GN
Barber
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004198:Disease Susceptibility; D005057:Eukaryotic Cells / Q000378:metabolism* / Q000821:virology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008969:Molecular Sequence Data; D051903:Nuclear Factor 45 Protein / Q000378:metabolism; D050779:Nuclear Factor 90 Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D012327:RNA Virus Infections / Q000276:immunology; D012328:RNA Viruses / Q000276:immunology; D016415:Sequence Alignment; D019892:eIF-2 Kinase / Q000378:metabolism*
D051903:Nuclear Factor 45 Protein; D050779:Nuclear Factor 90 Proteins; D019892:eIF-2 Kinase