STAT1β Is Not Dominant Negative and Is Capable of Contributing to Gamma Interferon-Dependent Innate Immunity

Abstract

The transcription factor STAT1 is essential for interferon (IFN)-mediated immunity in humans and mice. STAT1 function is tightly regulated, and both loss-and gain-of-function mutations result in severe immune diseases. The two alternatively spliced isoforms, STAT1␣ and STAT1␤, differ with regard to a C-terminal transactivation domain, which is absent in STAT1␤. STAT1␤ is considered to be transcriptionally inactive and to be a competitive inhibitor of STAT1␣. To investigate the functions of the STAT1 isoforms in vivo, we generated mice deficient for either STAT1␣ or STAT1␤. As expected, the functions of STAT1␣ and STAT1␤ in IFN-␣/␤-and IFN--dependent antiviral activity are largely redundant. In contrast to the current dogma, however, we found that STAT1␤ is transcriptionally active in response to IFN-␥. In the absence of STAT1␣, STAT1␤ shows more prolonged IFN-␥-induced phosphorylation and promoter binding. Both isoforms mediate protective, IFN-␥-dependent immunity against the bacterium Listeria monocytogenes, although with remarkably different efficiencies. Our data shed new light on the potential contributions of the individual STAT1 isoforms to STAT1-dependent immune responses. Knowledge of STAT1␤'s function will help fine-tune diagnostic approaches and help design more specific strategies to interfere with STAT1 activity.

Promoter Occupancy of STAT1 in Interferon Responses Is Regulated by Processive Transcription

“…BMDMs from STAT1 ␤/␤ mice exhibit reduced induction of GAS-driven genes in response to IFN-␥, but not all target genes are affected to the same extent (15). The expression of ISRE-driven genes is not grossly affected in STAT1 ␤/␤ BMDMs stimulated by IFN-␤, indicating that the ISGF3 complex is fully functional in these cells.…”

“…The expression of ISRE-driven genes is not grossly affected in STAT1 ␤/␤ BMDMs stimulated by IFN-␤, indicating that the ISGF3 complex is fully functional in these cells. The Irf1 and Socs1 genes were shown to be significantly less induced in IFN-␥-stimulated STAT1 ␤/␤ BMDMs than in IFN-␥-stimulated WT BMDMs (15). IFN-␤ treatment of STAT1 ␤/␤ BMDMs and analysis of pre-mRNA expression of Irf1 and Socs1 demonstrated that STAT1␤ homodimers were less transcriptionally active at these genes in type I IFN responses also ( Fig.…”

“…␤/␤ mice demonstrated that STAT1␤ homodimers retain significant transcriptional activity (15). BMDMs from STAT1 ␤/␤ mice exhibit reduced induction of GAS-driven genes in response to IFN-␥, but not all target genes are affected to the same extent (15).…”

“…To this end, we made use of BMDMs derived from mice expressing solely the STAT1␤ isoform (STAT1 ␤/␤ mice) (15). STAT1 occurs in cells in two isoforms: STAT1␣ is the fulllength isoform, whereas STAT1␤ is an isoform that lacks the Cterminal 38 amino acids but otherwise is identical with STAT1␣.…”

A20 inhibition of STAT1 expression in myeloid cells: a novel endogenous regulatory mechanism preventing development of enthesitis

“…A20 markedly suppressed the basal STAT1 protein levels (figure 3A, B). There are two alternatively spliced isoforms of STAT1 that can both participate in STAT1-dependent immunity: STAT1α and STAT1β 15. Both STAT1α and STAT1β protein levels were suppressed by A20, but the effect was more pronounced for STAT1β, leading to a lower STAT1α/STAT1β ratio in the absence of A20 (figure 3B).…”