A Novel Mechanism Underlying the Expression Regulation of An IFN-Inducible Gene RIG-G

The RIG-G gene, originally identified due to its markedly up-regulated transcriptional expression in acute promyelocytic leukemia cell line NB4 after treament with all-trans retinoic acid (ATRA) for 72 hours, is actually a member of Interferon (IFN)-inducible genes family. It acts as an important molecular mediator of the antiproliferative activity of IFN-related pathways through upregulation of cell cycle inhibitors p21 and p27. The fact of a synergistic induction of RIG-G mRNA in NB4 cells by the treatment with ATRA and IFNs implies a possible role of RIG-G in cross-talk between these two signaling pathways. However, the mechanism underlying the expression regulation of RIG-G gene remains unknown. In this work, we show that IRF-9 and STAT2 are two basic components required for RIG-G expression, although the tyrosine phosphorylation of STAT2 could further enhance the transactivation activity of the complex of IRF-9 and STAT2 by facilitating their interaction. In addition, we demonstrate the ability of ATRA to induce IFNa synthesis and secretion along with subsequent phosphorylation of STAT2 in NB4 cells, which may not only account for the dramatic expression of RIG-G after ATRA treatment but also provide a new view of signaling cross-talk between IFNa and ATRA. Moreover, we also observe that IRF-1, a primary response gene of both IFNa and ATRA, can modulate the transcription of RIG-G in both STAT2/IRF-9 dependent and independent ways. Taken together, we report for the first time that the complex of IRF-9 and STAT2 is sufficient for RIG-G expression even without the phosphorylation, and suggest a novel mechanism, different from the classical IFN-induced JAK-STAT pathways, through which IFN modulates its target genes. Our studies regarding the transcription regulation of RIG-G gene enrich our knowledge on IFN signaling pathways and will be beneficial to further better understanding of the complexity of biological responses to IFNs.