Homeodomain-interacting protein kinase 2, a novel autoimmune regulator interaction partner, modulates promiscuous gene expression in medullary thymic epithelial cells
| Autor: | Bruno Kyewski, Sonja Matt, Kristin Rattay, Janine Claude, Esmail Rezavandy, Jens Derbinski, Thomas G. Hofmann |
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| Rok vydání: | 2015 |
| Předmět: |
Transcriptional Activation
T cell Immunology Autoimmunity Thymus Gland Biology Protein Serine-Threonine Kinases Models Biological Mice Coactivator Gene expression Gene Order medicine Immunology and Allergy Animals Cluster Analysis Humans Antigens Phosphorylation Protein kinase A Gene Cell Nucleus Mice Knockout Gene Expression Profiling Epithelial Cells Autoimmune regulator Cell biology Protein Transport medicine.anatomical_structure Phenotype Gene Expression Regulation Genetic Loci Organ Specificity Knockout mouse Gene Targeting Cancer research Homeobox Carrier Proteins Protein Binding Transcription Factors |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 194(3) |
| ISSN: | 1550-6606 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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