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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

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STAT1β is not dominant negative and is capable of contributing to gamma interferon-dependent innate immunity.

Semper Christian C Leitner Nicole R NR Lassnig Caroline C Parrini Matthias M Mahlakõiv Tanel T Rammerstorfer Michael M Lorenz Karin K Rigler Doris D Müller Simone S Kolbe Thomas T Vogl Claus C Rülicke Thomas T Staeheli Peter P Decker Thomas T Müller Mathias M Strobl Birgit B

Molecular and cellular biology 20140407 12

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 ...[more]

PMID: 24710278

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Project description:Genes required for the lysosomal degradation pathway of autophagy play key roles in topologically distinct and physiologically important cellular processes. Some functions of ATG genes are independent of their role in degradative autophagy. One of the first described of these ATG gene-dependent, but degradative autophagy independent, processes is the requirement for a subset of ATG genes in interferon-γ (IFNγ)-induced inhibition of norovirus and Toxoplasma gondii replication. Herein, we identified additional genes that are required for, or that negatively regulate, this innate immune effector pathway. Enzymes in the UFMylation pathway negatively regulated IFNγ-induced inhibition of norovirus replication via effects of Ern1. IFNγ-induced inhibition of norovirus replication required Gate-16 (also termed GabarapL2), Wipi2b, Atg9a, Cul3, and Klhl9 but not Becn1 (encoding Beclin 1), Atg14, Uvrag, or Sqstm1. The phosphatidylinositol-3-phosphate and ATG16L1-binding domains of WIPI2B, as well as the ATG5-binding domain of ATG16L1, were required for IFNγ-induced inhibition of norovirus replication. Other members of the Cul3, Atg8, and Wipi2 gene families were not required, demonstrating exquisite specificity within these gene families for participation in IFNγ action. The generality of some aspects of this mechanism was demonstrated by a role for GATE-16 and WIPI2 in IFNγ-induced control of Toxoplasma gondii infection in human cells. These studies further delineate the genes and mechanisms of an ATG gene-dependent programmable form of cytokine-induced innate intracellular immunity. IMPORTANCE Interferon-γ (IFNγ) is a critical mediator of cell-intrinsic immunity to intracellular pathogens. Understanding the complex cellular mechanisms supporting robust interferon-γ-induced host defenses could aid in developing new therapeutics to treat infections. Here, we examined the impact of autophagy genes in the interferon-γ-induced host response. We demonstrate that genes within the autophagy pathway including Wipi2, Atg9, and Gate-16, as well as ubiquitin ligase complex genes Cul3 and Klhl9 are required for IFNγ-induced inhibition of murine norovirus (norovirus hereinafter) replication in mouse cells. WIPI2 and GATE-16 were also required for IFNγ-mediated restriction of parasite growth within the Toxoplasma gondii parasitophorous vacuole in human cells. Furthermore, we found that perturbation of UFMylation pathway components led to more robust IFNγ-induced inhibition of norovirus via regulation of endoplasmic reticulum (ER) stress. Enhancing or inhibiting these dynamic cellular components could serve as a strategy to control intracellular pathogens and maintain an effective immune response.

Dataset Information

STAT1? is not dominant negative and is capable of contributing to gamma interferon-dependent innate immunity.

Publications

STAT1β is not dominant negative and is capable of contributing to gamma interferon-dependent innate immunity.

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