Essential and non-redundant roles of p48 (ISGF3 gamma) and IRF-1 in both type I and type II interferon responses, as revealed by gene targeting studies.
BACKGROUND
Interferons (IFNs) are a class of cytokines which confer cellular resistance against viral infections. Type I (IFN-alpha and -beta) and type II (IFN-gamma) IFNs utilize distinct receptors, the stimulation of which results in the induction of downstream target genes. These target genes usually contain within their promoter region an IFN responsive element, termed ISRE (IFN stimulated response element) which binds a heterotrimeric transcription factor, ISGF3 (IFN-stimulated gene factor 3) consisting of p48 (ISGF3 gamma), Stat1 (Signal transducers and activators of transcription-1; alpha or beta), and Stat2. The ISRE sequence overlaps with that of IRF-E which binds another IFN-inducible factor, IRF-1 (IFN regulatory factor-1).


RESULTS
We generated mice lacking p48 by gene targeting. We show that p48 plays an essential role in both type I and type II IFN responses; activation of IFN-inducible genes and establishment of the antiviral state by IFN-alpha or -gamma are both severely impaired, and ISRE-binding activities induced by both IFNs are absent in the p48-negative embryonic fibroblasts (EFs). Furthermore, we generated mice deficient for both p48 and IRF-1 and found that at least one IFN-inducible gene is dependent on both factors.


CONCLUSIONS
p48 and IRF-1 do not perform redundant functions in the cell, but rather complement one another in both type I and II IFN responses.
Kimura
T
T
Department of Immunology, Faculty of Medicine, University of Tokyo, Japan.
Kadokawa
Y
Y
Harada
H
H
Matsumoto
M
M
Sato
M
M
Kashiwazaki
Y
Y
Tarutani
M
M
Tan
R S
RS
Takasugi
T
T
Matsuyama
T
T
Mak
T W
TW
Noguchi
S
S
Taniguchi
T
T
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D004247:DNA / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D018390:Gene Targeting; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I / Q000494:pharmacology*; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
D000998:Antiviral Agents; D017931:DNA Primers; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; C494227:IRF9 protein, human; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; C494258:Irf1 protein, mouse; C494228:Isgf3g protein, mouse; D010750:Phosphoproteins; D014157:Transcription Factors; D007371:Interferon-gamma; D004247:DNA