TRANSCRIPTIONAL INDUCTION BY DOUBLE-STRANDED-RNA IS MEDIATED BY INTERFERON-STIMULATED RESPONSE ELEMENTS WITHOUT ACTIVATION OF INTERFERON-STIMULATED GENE FACTOR-3
Sk. Bandyopadhyay et al., TRANSCRIPTIONAL INDUCTION BY DOUBLE-STRANDED-RNA IS MEDIATED BY INTERFERON-STIMULATED RESPONSE ELEMENTS WITHOUT ACTIVATION OF INTERFERON-STIMULATED GENE FACTOR-3, The Journal of biological chemistry, 270(33), 1995, pp. 19624-19629
Many genes induced by type I interferons (IFNs) are also induced by do
uble stranded (ds) RNA. In this study, we investigated the mechanism o
f this induction process. Using cell lines from which the type I IFN g
enes have been deleted, we established that induction by dsRNA of the
IFN-inducible 561 gene is direct and not mediated by the intermediate
synthesis of IFN. Unlike 561 mRNA, the IFN-inducible 6-16 mRNA was ind
uced poorly by dsRNA. Transfection studies demonstrated that the seque
nce difference between the core IFN-stimulated response elements (ISRE
s) of these two genes is not responsible for their differential induci
bility by dsRNA. A point mutation in the 561 ISRE that abolished its r
esponse to IFN-alpha also made it unresponsive to dsRNA, thus demonstr
ating that the ISRE is the relevant cis acting element for dsRNA signa
ling. The roles of different known ISRE-binding protein and tyrosine k
inases in transducing the signal elicited by dsRNA were evaluated in g
enetically altered cell lines, dsRNA failed to induce 561 mRNA in cell
s expressing an antisense RNA for interferon regulatory factor 1, wher
eas it was induced strongly in cells expressing the corresponding sens
e mRNA, 561 mRNA was also induced strongly by dsRNA, but not by IFN-al
pha, in mutant cell lines that do not express functional tyrosine kina
ses Tyk2 or JAK1 or ISRE binding protein, p48, or STATE, all of which
are required for LFN-alpha signaling. However, in cells devoid of func
tional STAT1, which is also required for IFN-alpha signaling, the indu
ction of 561 mRNA by dsRNA was very low. Expression of transfected STA
T1 alpha protein, but not of STAT1 beta protein, in these cells greatl
y enhanced the dsRNA inducibility of the 561 gene. These studies indic
ate that the major ISRE-mediated signaling pathway used by dsRNA requi
res interferon regulatory factor 1 and STAT1 alpha. This pathway, howe
ver, does not require the other known cytoplasmic components used for
IFN-alpha signaling.