STAT1β is not dominant negative and is capable of contributing to gamma interferon-dependent innate immunity.
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.
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
Christian
C
Semper
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
Nicole R
NR
Leitner
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria University Center Biomodels Austria, University of Veterinary Medicine Vienna, Vienna, Austria.
Caroline
C
Lassnig
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
Matthias
M
Parrini
Institute of Virology, University Medical Center Freiburg, Freiburg, Germany Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Freiburg, Germany.
Tanel
T
Mahlakõiv
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
Michael
M
Rammerstorfer
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
Karin
K
Lorenz
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
Doris
D
Rigler
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
Simone
S
Müller
University Center Biomodels Austria, University of Veterinary Medicine Vienna, Vienna, Austria Institute of Biotechnology in Animal Production, Department of Agrobiotechnology IFA-Tulln, University of Natural Resources and Life Sciences, Vienna, Austria.
Thomas
T
Kolbe
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
Claus
C
Vogl
Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.
Thomas
T
Rülicke
Institute of Virology, University Medical Center Freiburg, Freiburg, Germany.
Peter
P
Staeheli
Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
Thomas
T
Decker
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria University Center Biomodels Austria, University of Veterinary Medicine Vienna, Vienna, Austria.
Mathias
M
Müller
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria birgit.strobl@vetmeduni.ac.at.
Birgit
B
Strobl
D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055879:Gene Knock-In Techniques; D005799:Genes, Dominant; D006566:Herpesviridae Infections / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate / Q000187:drug effects*; D016899:Interferon-beta / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D008087:Listeria / Q000187:drug effects / Q000502:physiology; D008088:Listeriosis / Q000276:immunology / Q000473:pathology; D051379:Mice; D018146:Muromegalovirus / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
D020033:Protein Isoforms; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D019000:Phosphotyrosine; D016899:Interferon-beta; D007371:Interferon-gamma