STAT1? 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.

SUBMITTER: Semper C 

PROVIDER: S-EPMC4054301 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature