The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance
The transcriptional regulator Aire is required for central tolerance, but how it manages to target tissue-specific genes is unclear. Anderson and colleagues show that Aire achieves such targeting by coopting the ATF7ip-MBD1 repressor complex. The maintenance of immunological tolerance requires the d...
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Published in | Nature immunology Vol. 15; no. 3; pp. 258 - 265 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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New York
Nature Publishing Group US
01.03.2014
Nature Publishing Group |
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Online Access | Get full text |
ISSN | 1529-2908 1529-2916 1529-2916 |
DOI | 10.1038/ni.2820 |
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Abstract | The transcriptional regulator Aire is required for central tolerance, but how it manages to target tissue-specific genes is unclear. Anderson and colleagues show that Aire achieves such targeting by coopting the ATF7ip-MBD1 repressor complex.
The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover,
Mbd1
−/−
mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance. |
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AbstractList | The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, Mbd1(-/-) mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance. The transcriptional regulator Aire is required for central tolerance, but how it manages to target tissue-specific genes is unclear. Anderson and colleagues show that Aire achieves such targeting by coopting the ATF7ip-MBD1 repressor complex. The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, Mbd1 −/− mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance. The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, Mbd1(-/-) mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance.The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, Mbd1(-/-) mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance. The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, [Mbd1.sup.-/-] mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance. The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, Mbd1 super(-/-) mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance. |
Audience | Academic |
Author | Metzger, Todd Fasano, Kayla Erle, David J Greer, Alexandra Cortez, Jessica T Khan, Imran S Martinez-Llordella, Marc Pollack, Joshua L Anderson, Mark S Su, Maureen Fan, Una Waterfield, Michael |
Author_xml | – sequence: 1 givenname: Michael surname: Waterfield fullname: Waterfield, Michael organization: Diabetes Center, University of California San Francisco, Department of Pediatrics, University of California San Francisco – sequence: 2 givenname: Imran S surname: Khan fullname: Khan, Imran S organization: Diabetes Center, University of California San Francisco – sequence: 3 givenname: Jessica T surname: Cortez fullname: Cortez, Jessica T organization: Diabetes Center, University of California San Francisco – sequence: 4 givenname: Una surname: Fan fullname: Fan, Una organization: Diabetes Center, University of California San Francisco – sequence: 5 givenname: Todd surname: Metzger fullname: Metzger, Todd organization: Diabetes Center, University of California San Francisco – sequence: 6 givenname: Alexandra surname: Greer fullname: Greer, Alexandra organization: Department of Microbiology & Immunology, University of California San Francisco – sequence: 7 givenname: Kayla surname: Fasano fullname: Fasano, Kayla organization: Diabetes Center, University of California San Francisco – sequence: 8 givenname: Marc surname: Martinez-Llordella fullname: Martinez-Llordella, Marc organization: Department of Liver Sciences, Division of Transplantation Immunology & Mucosal Biology, Institute of Liver Studies, King's College London – sequence: 9 givenname: Joshua L surname: Pollack fullname: Pollack, Joshua L organization: Department of Medicine, University of California San Francisco – sequence: 10 givenname: David J surname: Erle fullname: Erle, David J organization: Department of Medicine, University of California San Francisco – sequence: 11 givenname: Maureen surname: Su fullname: Su, Maureen organization: Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill – sequence: 12 givenname: Mark S surname: Anderson fullname: Anderson, Mark S email: manderson@diabetes.ucsf.edu organization: Diabetes Center, University of California San Francisco, Department of Medicine, University of California San Francisco |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24464130$$D View this record in MEDLINE/PubMed |
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Snippet | The transcriptional regulator Aire is required for central tolerance, but how it manages to target tissue-specific genes is unclear. Anderson and colleagues... The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific... |
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SubjectTerms | 13 13/1 13/105 13/109 13/31 13/44 13/51 13/89 631/250/38 AIRE Protein Animals Autoantigens - immunology Biomedicine Central Tolerance - genetics Central Tolerance - immunology DNA-Binding Proteins - genetics DNA-Binding Proteins - immunology Flow Cytometry Gene Expression Regulation - immunology HEK293 Cells Humans Immune system Immune Tolerance Immunoblotting Immunology Immunoprecipitation Infectious Diseases Mice Mice, Inbred C57BL Mice, Knockout Oligonucleotide Array Sequence Analysis Physiological research Properties Protein Binding Repressor Proteins - genetics Repressor Proteins - immunology Reverse Transcriptase Polymerase Chain Reaction Transcription factors Transcription Factors - genetics Transcription Factors - immunology Transfection Two-Hybrid System Techniques |
Title | The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance |
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