Contribution of the STAT1alpha and STAT1beta isoforms to IFN-gamma mediated innate immunity

The transcription factor STAT1 is essential for interferon- (IFN) mediated protective immunity in humans and mice. Two splice isoforms of STAT1, STAT1 and STAT1, differ with regard to a C-terminal transactivation domain, which is absent in STAT1. Dimers of STAT1 are therefore considered transcriptionally inactive and potential competitive inhibitors of STAT1. Contrasting this view, generation and analysis of mice deficient for either STAT1 or STAT1 demonstrated transcriptional activity of the STAT1 isoform and its enhancement of innate immunity. Gene expression profiling in primary cells revealed overlapping, but also non-redundant and gene-specific activities of STAT1 and STAT1 in response to IFN. Consistently, both isoforms mediated protective, IFN-dependent immunity against the bacterium Listeria monocytogenes, although with remarkably different efficiency. In contrast, STAT1 and STAT1 were largely redundant for transcriptional responses to IFN/ and for IFN/-dependent antiviral activity. Collectively, our data shed new light on how STAT1 isoforms contribute to antimicrobial immunity.

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Semper C, Leitner NR, Lassnig C, Parrini M, Mahlakõiv T, Rammerstorfer M, Lorenz K, Rigler D, Müller S, Kolbe T, Vogl C, Rülicke T, Staeheli P, Decker T, Müller M, Strobl B