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, STAT1α and STAT1β, differ with regard to a C-terminal transactivation domain, which is absent in STAT1β. STAT1β is considered to be transcriptionally inactive and to be a competitive inhibitor of STAT1α. To investigate the functions of the STAT1 isoforms in vivo, we generated mice deficient for either STAT1α or STAT1β. As expected, the functions of STAT1α and STAT1β in IFN-α/β- and IFN-λ-dependent antiviral activity are largely redundant. In contrast to the current dogma, however, we found that STAT1β is transcriptionally active in response to IFN-γ. In the absence of STAT1α, STAT1β shows more prolonged IFN-γ-induced phosphorylation and promoter binding. Both isoforms mediate protective, IFN-γ-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 STAT1β's function will help fine-tune diagnostic approaches and help design more specific strategies to interfere with STAT1 activity.

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SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00295-14.

ACKNOWLEDGMENTS

This work was supported by Austrian Science Fund (FWF) grants FWF-P25642-B22 to B.S. and SFB-F28 to B.S., M.M., and T.D. T.M. was supported in part by the Excellence Initiative of the German Research Foundation (GSC-4, Spemann Graduate School). M.P. participated in the FWF-funded DK-IAI (W1212).

We declare that we have no conflicts of interest.

We thank Ingeborg Klymiuk for help with the microarray analysis. We are grateful to Pavel Kovarik for fruitful discussions throughout the project and to Graham Tebb for critically reading and editing the manuscript.