STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling

Begitt, Andreas; Droescher, Mathias; Meyer, Thomas; Schmid, Christoph D.; Baker, Michelle; Antunes, Filipa; Knobeloch, Klaus–Peter; Owen, Markus R.; Naumann, Ronald; Decker, Thomas; Vinkemeier, Uwe

doi:10.1038/ni.2794

Cited by 81 publications

(82 citation statements)

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“…The ability of STAT1␤ to induce Irf1 may account for ISRE-regulated gene induction during secondary responses. It is unclear how STAT1␤ induces Irf1, but the mechanism may involve a recently identified ISRE around 7 kb upstream of the transcription start site of the Irf1 gene (66). However, STAT1␤ is not able to perform all the functions of STAT1␣, and our data reveal that over 16% and 9% of genes are induced only by STAT1␣.…”

Section: Time After Treatment Ti Ti Ti Ft Ft Ft T T T T T T T T Tmentioning

confidence: 66%

STAT1β Is Not Dominant Negative and Is Capable of Contributing to Gamma Interferon-Dependent Innate Immunity

Semper

Leitner

Lassnig

et al. 2014

Molecular and Cellular Biology

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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.

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Section: Time After Treatment Ti Ti Ti Ft Ft Ft T T T T T T T T Tmentioning

confidence: 66%

STAT1β Is Not Dominant Negative and Is Capable of Contributing to Gamma Interferon-Dependent Innate Immunity

Semper

Leitner

Lassnig

et al. 2014

Molecular and Cellular Biology

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“…55 Distinct type I and II IFNs are used in different contexts for hematopoietic development. 56,57 Previous work in zebrafish and mice suggest that IFN-g promotes HSC emergence in midgestation embryos but zebrafish lack an IFN-a homolog, thus leaving the role of this type I IFN unexplored. 16,18 Whereas IFN-g promotes HSC emergence, our data argue that IFN-a promotes partial AGM HSC maturation.…”

Section: Discussionmentioning

confidence: 99%

Interferon-α signaling promotes embryonic HSC maturation

Kim

Canver

Rhee

et al. 2016

Blood

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In the developing mouse embryo, the first hematopoietic stem cells (HSCs) arise in the aorta-gonad-mesonephros (AGM) and mature as they transit through the fetal liver (FL). Compared with FL and adult HSCs, AGM HSCs have reduced repopulation potential in irradiated adult transplant recipients but mechanisms underlying this deficiency in AGM HSCs are poorly understood. By co-expression gene network analysis, we deduced that AGM HSCs show lower levels of interferon-a (IFN-a)/Jak-Stat1-associated gene expression than FL HSCs. Treatment of AGM HSCs with IFN-a enhanced long-term hematopoietic engraftment and donor chimerism. Conversely, IFN-a receptor-deficient AGMs (Ifnar1 2/2 ), had significantly reduced donor chimerism. We identify adenine-thymine-rich interactive domain-3a (Arid3a), a factor essential for FL and B lymphopoiesis, as a key transcriptional co-regulator of IFN-a/Stat1 signaling. Arid3a occupies the genomic loci of Stat1 as well as several IFN-a effector genes, acting to regulate their expression. Accordingly, Arid3a 2/2 AGM HSCs had significantly reduced transplant potential, which was rescued by IFN-a treatment. Our results implicate the inflammatory IFN-a/ Jak-Stat pathway in the developmental maturation of embryonic HSCs, whose manipulation may lead to increased potency of reprogrammed HSCs for transplantation. (Blood. 2016;128(2):204-216)

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“…Indeed, in response to IFN-a, STAT2 was shown to form, independently from STAT1, a complex with IRF9 (28) that binds ISRE and mediates ISG expression (29). Also, it was shown that whereas STAT1 cooperativity is essential for IFN-g response, it is dispensable for IFN-a signaling (30). Very recently, it has been reported that IFN-a activates the STAT2/IRF9 complex that forms an ISGF3-like response without STAT1 and generates an antiviral response in the absence of STAT1 (31).…”

Section: Discussionmentioning

confidence: 99%

“…5E). In this experiment, we observed two different levels of inhibition: one intermediate, between 30 and 50% (gray), and a nearly complete inhibition of ∼80-90% (black). These two phenotypes illustrate the dual effect of SUMO paralogs on IFN-g signaling, by acting both on STAT1 phosphorylation and PML stability.…”

Section: Sumo1 or Sumo3 Expression Reduces Ifn-g But Not Ifn-a Transcmentioning

confidence: 99%

Small Ubiquitin-like Modifier Alters IFN Response

Maarifi

Maroui

Dutrieux

et al. 2015

The Journal of Immunology

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IFNs orchestrate immune defense through induction of hundreds of genes. Small ubiquitin-like modifier (SUMO) is involved in various cellular functions, but little is known about its role in IFN responses. Prior work identified STAT1 SUMOylation as an important mode of regulation of IFN-γ signaling. In this study, we investigated the roles of SUMO in IFN signaling, gene expression, protein stability, and IFN-induced biological responses. We first show that SUMO overexpression leads to STAT1 SUMOylation and to a decrease in IFN-induced STAT1 phosphorylation. Interestingly, IFNs exert a negative retrocontrol on their own signaling by enhancing STAT1 SUMOylation. Furthermore, we show that expression of each SUMO paralog inhibits IFN-γ–induced transcription without affecting that of IFN-α. Further, we focused on IFN-induced gene products associated to promyelocytic leukemia (PML) nuclear bodies, and we show that neither IFN-α nor IFN-γ could increase PML and Sp100 protein expression because they enhanced their SUMO3 conjugation and subsequent proteasomal degradation. Because it is known that SUMO3 is important for the recruitment of RING finger protein 4, a poly–SUMO-dependent E3 ubiquitin ligase, and that PML acts as a positive regulator of IFN-induced STAT1 phosphorylation, we went on to show that RING finger protein 4 depletion stabilizes PML and is correlated with a positive regulation of IFN signaling. Importantly, inhibition of IFN signaling by SUMO is associated with a reduction of IFN-induced apoptosis, cell growth inhibition, antiviral defense, and chemotaxis. Conversely, inhibition of SUMOylation results in higher IFN-γ–induced STAT1 phosphorylation and biological responses. Altogether, our results uncover a new role for SUMO in the modulation of IFN response.

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STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling

Cited by 81 publications

References 50 publications

STAT1β Is Not Dominant Negative and Is Capable of Contributing to Gamma Interferon-Dependent Innate Immunity

STAT1β Is Not Dominant Negative and Is Capable of Contributing to Gamma Interferon-Dependent Innate Immunity

Interferon-α signaling promotes embryonic HSC maturation

Small Ubiquitin-like Modifier Alters IFN Response

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