Functional interaction of AIRE with PIAS1 in transcriptional regulation

Ilmarinen, Tanja; Kangas, Hannele; Kytomaa, Taina; Eskelin, Petra; Saharinen, Juha; Seeler, Jacob-S.; Tanhuanpaa, Kirnmo; Chan, Fung-Yee; Slattery, Robyn Maree; Alakurtti, Kirsi; Palvimo, Jorma J.; Ulmanen, Ismo

doi:10.1016/j.molimm.2007.10.045

Cited by 32 publications

(38 citation statements)

References 75 publications

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“…We demonstrate here that AIRE-deficient murine BMDCs produce excess BAFF upon IFN-␥ stimulation, indicating a cell-intrinsic effect of AIRE in the periphery. The recently published functional interaction between AIRE and PIAS1, a negative regulator of STAT1 signaling, supports our finding that the absence of AIRE can result in augmented signaling downstream of the IFN-␥ receptor (28). As a consequence, excess BAFF is produced by Aire Ϫ/Ϫ DCs, leading to increased activation of B cells in the periphery (Fig.…”

Section: Discussionsupporting

confidence: 89%

“…Thus, our findings suggested that the IFN-␥ stimulation caused augmented signaling via the IFN-␥ receptor in AIRE-deficient DCs, leading to excess production of BAFF. Interestingly, a recent publication demonstrates a functional interaction between AIRE and the transcriptional co-activator protein inhibitor of activated STAT1 (PIAS1) in the nucleus (28). Upon IFN-␥ receptor stimulation, STAT1 becomes tyrosine phosphorylated and translocates into the nucleus where it activates transcription.…”

Section: Aire Is Involved In the Ifn-␥ Receptor Signaling Pathway In mentioning

confidence: 99%

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AIRE regulates T-cell-independent B-cell responses through BAFF

Lindh

Lind

Lindmark

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Autoimmune polyendocrine syndrome type I (APS I) results in multiple endocrine organ destruction and is caused by mutations in the autoimmune regulator gene (AIRE). APS I is characterized by circulating tissue-specific autoantibodies, and the presence of these antibodies is often predictive of organ destruction. The importance of AIRE in ensuring central tolerance by regulating the negative selection of autoreactive T cells has been shown clearly. However, in Aire ؊/؊ mice the phenotype (i.e., autoantibodies, liver infiltrates of B cells, splenomegaly, and marginal zone B-cell lymphoma) is predominantly B-cell mediated, suggesting an exaggerated activation of B cells. We have studied T-cell-independent B-cell responses in the absence of AIRE and found that Aire ؊/؊ mice have an increased response against T-cell-independent type II antigens. We linked this exaggerated response to the elevated serum levels of the B-cell-activating factor of the TNF family (BAFF) that were found both in APS I patients and in Aire ؊/؊ mice. Transfer of Aire ؊/؊ bone marrow into irradiated nude mice resulted in increased percentage of BAFF-expressing antigenpresenting cells compared with wt bone marrow, suggesting a T-cell-independent mechanism behind our findings. Furthermore, in vitro experiments showed that AIRE-deficient murine bone marrowderived dendritic cells produced significantly more BAFF than wt cells when stimulated with IFN-␥ but not when stimulated with IL-10. Our results suggest a cell-intrinsic role for AIRE in peripheral dendritic cells by regulating IFN-␥-receptor signaling and point toward complementary mechanisms by which AIRE is involved in maintaining tolerance.autoimmunity ͉ tolerance

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Section: Discussionsupporting

confidence: 89%

Section: Aire Is Involved In the Ifn-␥ Receptor Signaling Pathway In mentioning

confidence: 99%

AIRE regulates T-cell-independent B-cell responses through BAFF

Lindh

Lind

Lindmark

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…We identified five interaction partners, two of which, PIAS1 and Ubc9, had been previously reported to interact with Aire (33,34). We provide evidence that HIPK2, a known regulator of cell fate and transcription, is a novel Aire binding protein, adding to the growing list of Aire binding partners and Aire "allies" (7-9, 12, 16, 17).…”

Section: Discussionmentioning

confidence: 72%

“…The SUMO conjugating enzyme Ubc9 and the SUMO E3 ligase PIAS1 actively catalyze the SUMOylation of substrates, whereas DeSi-1 functions as an antagonist of SUMOylation by catalyzing deconjugation of SUMO from substrate proteins. Yet, PIAS, previously identified as an AIRE interacting protein, does not lead to SUMO modification of AIRE (33). However, ectopic expression of PIAS1 attracted AIRE to SUMO-1-containing nuclear complexes, which suggests that AIRE function may be controlled by the SUMO pathway, which can modulate protein localization and plays a prominent role in transcriptional regulation (41).…”

Section: Discussionmentioning

confidence: 94%

Homeodomain-Interacting Protein Kinase 2, a Novel Autoimmune Regulator Interaction Partner, Modulates Promiscuous Gene Expression in Medullary Thymic Epithelial Cells

Rattay

Claude

Rezavandy

et al. 2015

The Journal of Immunology

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Promiscuous expression of a plethora of tissue-restricted Ags (TRAs) by medullary thymic epithelial cells (mTECs) plays an essential role in T cell tolerance. Although the cellular mechanisms by which promiscuous gene expression (pGE) imposes T cell tolerance have been well characterized, the underlying molecular mechanisms remain poorly understood. The autoimmune regulator (AIRE) is to date the only validated molecule known to regulate pGE. AIRE is part of higher-order multiprotein complexes, which promote transcription, elongation, and splicing of a wide range of target genes. How AIRE and its partners mediate these various effects at the molecular level is still largely unclear. Using a yeast two-hybrid screen, we searched for novel AIRE-interacting proteins and identified the homeodomain-interacting protein kinase 2 (HIPK2) as a novel partner. HIPK2 partially colocalized with AIRE in nuclear bodies upon cotransfection and in human mTECs in situ. Moreover, HIPK2 phosphorylated AIRE in vitro and suppressed the coactivator activity of AIRE in a kinase-dependent manner. To evaluate the role of Hipk2 in modulating the function of AIRE in vivo, we compared whole-genome gene signatures of purified mTEC subsets from TEC-specific Hipk2 knockout mice with control mice and identified a small set of differentially expressed genes. Unexpectedly, most differentially expressed genes were confined to the CD80lo mTEC subset and preferentially included AIRE-independent TRAs. Thus, although it modulates gene expression in mTECs and in addition affects the size of the medullary compartment, TEC-specific HIPK2 deletion only mildly affects AIRE-directed pGE in vivo.

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“…[75][76][77] However, AIRE also contains two PHD (Plant HomeoDomain)-type zinc fingers that confer its ability to associate with numerous protein partners and that are essential for regulation of gene expression. [78][79][80] These PHD domains associate with histone 3 at unmethylated lysine 4 residues (H3K4me0), which are typically within transcriptionally inactive chromatin regions, and in combination with DNA-dependent protein kinase, appear to promote subsequent transcription. [81][82][83] Consistent with this model of transcriptional regulation, AIREregulated genes are chromosomally clustered and stochastically expressed.…”

Section: Aire Regulates Promiscuous Gene Expression In Mtecmentioning

confidence: 99%

Ovarian autoimmune disease: clinical concepts and animal models

et al. 2014

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The ovary is not an immunologically privileged organ, but a breakdown in tolerogenic mechanisms for ovary-specific antigens has disastrous consequences on fertility in women, and this is replicated in murine models of autoimmune disease. Isolated ovarian autoimmune disease is rare in women, likely due to the severity of the disease and the inability to transmit genetic information conferring the ovarian disease across generations. Nonetheless, autoimmune oophoritis is often observed in association with other autoimmune diseases, particularly autoimmune adrenal disease, and takes a toll on both society and individual health. Studies in mice have revealed at least two mechanisms that protect the ovary from autoimmune attack. These mechanisms include control of autoreactive T cells by thymus-derived regulatory T cells, as well as a role for the autoimmune regulator (AIRE), a transcriptional regulator that induces expression of tissue-restricted antigens in medullary thymic epithelial cells during development of T cells. Although the latter mechanism is incompletely defined, it is well established that failure of either results in autoimmune-mediated targeting and depletion of ovarian follicles. In this review, we will address the clinical features and consequences of autoimmune-mediated ovarian infertility in women, as well as the possible mechanisms of disease as revealed by animal models.

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Functional interaction of AIRE with PIAS1 in transcriptional regulation

Cited by 32 publications

References 75 publications

AIRE regulates T-cell-independent B-cell responses through BAFF

AIRE regulates T-cell-independent B-cell responses through BAFF

Homeodomain-Interacting Protein Kinase 2, a Novel Autoimmune Regulator Interaction Partner, Modulates Promiscuous Gene Expression in Medullary Thymic Epithelial Cells

Ovarian autoimmune disease: clinical concepts and animal models

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