DAXX is a new AIRE-interacting protein.

Meloni, Alessandra; Fiorillo, Edoardo; Corda, D.; Incani, Federica; Serra, Mauro; Contini, Andrea; Cao, Antonio; Rosatelli, Maria Cristina

doi:10.1074/jbc.a109.037747

Cited by 10 publications

(17 citation statements)

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“…2B). Coexpression of wild-type HIPK2 resulted in a dose-dependent reduction of the AIRE-driven reporter gene activity, indicating that HIPK2 represses AIRE-controlled transactivation, as has been previously reported for DAXX (38). Of note, this repressive effect of HIPK2 required its kinase activity, as a kinase-deficient HIPK2 point mutant (HIPK2 K221A) failed to suppress the coactivator function of AIRE (Fig.…”

Section: Hipk2 Phosphorylates Aire In Vitro and Represses Its Transcrmentioning

confidence: 63%

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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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Section: Hipk2 Phosphorylates Aire In Vitro and Represses Its Transcrmentioning

confidence: 63%

“…Notably, AIRE and HIPK2 share some of their interacting proteins including the transcriptional cofactors CBP and DAXX, two factors shown to be recruited, similar to AIRE and HIPK2, to PML NBs in response to cellular stress (36,38,40,(42)(43)(44). HIPK2 interacts with CBP and stimulates the acetyltransferase activity of CBP/p300 (36,45).…”

Section: Discussionmentioning

confidence: 99%

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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“…[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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“…DAXX is known to bind histones and recruit histone deacetylases and also binds and recruits other proteins (Pax3, Pax5, p53, glucocorticoid receptor, and HDAC). Together, the actions of DAXX and its protein complex implicate Aire in epigenetics and can alter its accessibility to other transcriptional targets …”

Section: Molecular Mechanisms Of Airementioning

confidence: 99%

Central tolerance to self revealed by the autoimmune regulator

Chan

Anderson

2015

Annals of the New York Academy of Sciences

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The autoimmune regulator (Aire) was initially identified as the gene causing multiorgan system autoimmunity in humans, and deletion of this gene in mice also resulted in organ-specific autoimmunity. Aire regulates the expression of tissue-specific antigens (TSAs) in medullary thymic epithelial cells (mTECs), which play a critical role in the negative selection of autoreactive T cells and the generation of regulatory T cells. More recently, the role of Aire in the development of mTECs have helped elucidate its ability to present the spectrum of TSAs needed to prevent autoimmunity. Molecular characterization of the functional domains of Aire have revealed multiple binding partners that assist Aire’s function in altering gene transcription and chromatin remodeling. These recent advances have further highlighted the importance of Aire in central tolerance.

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DAXX is a new AIRE-interacting protein.

Cited by 10 publications

References 0 publications

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

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

Central tolerance to self revealed by the autoimmune regulator

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