Interaction of human tRNA-dihydrouridine synthase-2 with interferon-induced protein kinase PKR.
PKR is an interferon (IFN)-induced protein kinase, which is involved in regulation of antiviral innate immunity, stress signaling, cell proliferation and programmed cell death. Although a low amount of PKR is expressed ubiquitously in all cell types in the absence of IFNs, PKR expression is induced at transcriptional level by IFN. PKR's enzymatic activity is activated by its binding to one of its activators. Double-stranded (ds) RNA, protein activator PACT and heparin are the three known activators of PKR. Activation of PKR in cells leads to a general block in protein synthesis due to phosphorylation of eIF2alpha on serine 51 by PKR. PKR activation is regulated very tightly in mammalian cells and a prolonged activation of PKR leads to apoptosis. Thus, positive and negative regulation of PKR activation is important for cell viability and function. The studies presented here describe human dihydrouridine synthase-2 (hDUS2) as a novel regulator of PKR. We originally identified hDUS2 as a protein interacting with PACT in a yeast two-hybrid screen. Further characterization revealed that hDUS2 also interacts with PKR through its dsRNA binding/dimerization domain and inhibits its kinase activity. Our results suggest that hDUS2 may act as a novel inhibitor of PKR in cells.
Mittelstadt
Megan
M
Department of Biological Sciences, University of South Carolina Columbia, SC 29208, USA.
Frump
Andrea
A
Khuu
Tuanh
T
Fowlkes
Vennece
V
Handy
Indhira
I
Patel
Chandrashekhar V
CV
Patel
Rekha C
RC
D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D017124:Conserved Sequence; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012330:RNA, Double-Stranded / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
C104647:PRKRA protein, human; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; D010088:Oxidoreductases; C526987:tRNA dihydrouridine synthase-2, human; D019892:eIF-2 Kinase