title: Homeodomain-interacting protein kinase 2, a novel autoimmune regulator interaction partner, modulates promiscuous gene expression in medullary thymic epithelial cells.
abstract: 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 CD80(lo) 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.
authors.affiliation: Division of Developmental Immunobiology, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany; and.
authors.forename: Kristin
authors.initials: K
authors.lastname: Rattay
authors.affiliation: Division of Developmental Immunobiology, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany; and.
authors.forename: Janine
authors.initials: J
authors.lastname: Claude
authors.affiliation: Division of Developmental Immunobiology, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany; and.
authors.forename: Esmail
authors.initials: E
authors.lastname: Rezavandy
authors.affiliation: Zelluläre Seneszenz-Gruppe, Deutsches Krebsforschungszentrum-Zentrum für Molekulare Biologie Allianz, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Matt
authors.affiliation: Zelluläre Seneszenz-Gruppe, Deutsches Krebsforschungszentrum-Zentrum für Molekulare Biologie Allianz, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany b.kyewski@dkfz-heidelberg.de t.hofmann@dkfz-heidelberg.de.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hofmann
authors.affiliation: Division of Developmental Immunobiology, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany; and b.kyewski@dkfz-heidelberg.de t.hofmann@dkfz-heidelberg.de.
authors.forename: Bruno
authors.initials: B
authors.lastname: Kyewski
authors.affiliation: Division of Developmental Immunobiology, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany; and.
authors.forename: Jens
authors.initials: J
authors.lastname: Derbinski
mesh_terms: D000818:Animals; D000941:Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D016000:Cluster Analysis; D004847:Epithelial Cells / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D023061:Gene Order; D018390:Gene Targeting; D056426:Genetic Loci; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D000096927:AIRE Protein
chemical_list: D000941:Antigens; D002352:Carrier Proteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D000096927:AIRE Protein; C115114:HIPK2 protein, human; C492003:Hipk2 protein, mouse