Cargando…

Patient mutation in AIRE disrupts P-TEFb binding and target gene transcription

Autoimmune regulator (AIRE) is a transcription factor that induces the expression of a large subset of otherwise strictly tissue restricted antigens in medullary thymic epithelial cells, thereby enabling their presentation to developing T cells for negative selection. Mutations in AIRE lead to autoi...

Descripción completa

Detalles Bibliográficos
Autores principales: Žumer, Kristina, Plemenitaš, Ana, Saksela, Kalle, Peterlin, B. Matija
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185428/
https://www.ncbi.nlm.nih.gov/pubmed/21724609
http://dx.doi.org/10.1093/nar/gkr527
_version_ 1782213211934687232
author Žumer, Kristina
Plemenitaš, Ana
Saksela, Kalle
Peterlin, B. Matija
author_facet Žumer, Kristina
Plemenitaš, Ana
Saksela, Kalle
Peterlin, B. Matija
author_sort Žumer, Kristina
collection PubMed
description Autoimmune regulator (AIRE) is a transcription factor that induces the expression of a large subset of otherwise strictly tissue restricted antigens in medullary thymic epithelial cells, thereby enabling their presentation to developing T cells for negative selection. Mutations in AIRE lead to autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a rare monogenetic disease. Although it has been reported that AIRE interacts with proteins involved in nuclear transport, DNA-damage response, chromatin remodeling, transcription and pre-mRNA-splicing, the precise mechanism of AIRE-induced tissue restricted antigen expression has remained elusive. In this study, we investigated an APECED patient mutation that causes the loss of the extreme C-terminus of AIRE and found that this mutant protein is transcriptionaly inactive. When tethered heterologously to DNA, this domain could stimulate transcription and splicing by itself. Moreover, the loss of this C-terminus disrupted interactions with the positive transcription elongation factor b (P-TEFb). Via P-TEFb, AIRE increased levels of RNA polymerase II on and enhanced pre-mRNA splicing of heterologous and endogenous target genes. Indeed, the inhibition of CDK9, the kinase subunit of P-TEFb, inhibited AIRE-induced pre-mRNA splicing of these genes. Thus, AIRE requires P-TEFb to activate transcription elongation and co-transcriptional processing of target genes.
format Online
Article
Text
id pubmed-3185428
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-31854282011-10-04 Patient mutation in AIRE disrupts P-TEFb binding and target gene transcription Žumer, Kristina Plemenitaš, Ana Saksela, Kalle Peterlin, B. Matija Nucleic Acids Res Gene Regulation, Chromatin and Epigenetics Autoimmune regulator (AIRE) is a transcription factor that induces the expression of a large subset of otherwise strictly tissue restricted antigens in medullary thymic epithelial cells, thereby enabling their presentation to developing T cells for negative selection. Mutations in AIRE lead to autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a rare monogenetic disease. Although it has been reported that AIRE interacts with proteins involved in nuclear transport, DNA-damage response, chromatin remodeling, transcription and pre-mRNA-splicing, the precise mechanism of AIRE-induced tissue restricted antigen expression has remained elusive. In this study, we investigated an APECED patient mutation that causes the loss of the extreme C-terminus of AIRE and found that this mutant protein is transcriptionaly inactive. When tethered heterologously to DNA, this domain could stimulate transcription and splicing by itself. Moreover, the loss of this C-terminus disrupted interactions with the positive transcription elongation factor b (P-TEFb). Via P-TEFb, AIRE increased levels of RNA polymerase II on and enhanced pre-mRNA splicing of heterologous and endogenous target genes. Indeed, the inhibition of CDK9, the kinase subunit of P-TEFb, inhibited AIRE-induced pre-mRNA splicing of these genes. Thus, AIRE requires P-TEFb to activate transcription elongation and co-transcriptional processing of target genes. Oxford University Press 2011-10 2011-06-30 /pmc/articles/PMC3185428/ /pubmed/21724609 http://dx.doi.org/10.1093/nar/gkr527 Text en © The Author(s) 2011. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Gene Regulation, Chromatin and Epigenetics
Žumer, Kristina
Plemenitaš, Ana
Saksela, Kalle
Peterlin, B. Matija
Patient mutation in AIRE disrupts P-TEFb binding and target gene transcription
title Patient mutation in AIRE disrupts P-TEFb binding and target gene transcription
title_full Patient mutation in AIRE disrupts P-TEFb binding and target gene transcription
title_fullStr Patient mutation in AIRE disrupts P-TEFb binding and target gene transcription
title_full_unstemmed Patient mutation in AIRE disrupts P-TEFb binding and target gene transcription
title_short Patient mutation in AIRE disrupts P-TEFb binding and target gene transcription
title_sort patient mutation in aire disrupts p-tefb binding and target gene transcription
topic Gene Regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185428/
https://www.ncbi.nlm.nih.gov/pubmed/21724609
http://dx.doi.org/10.1093/nar/gkr527
work_keys_str_mv AT zumerkristina patientmutationinairedisruptsptefbbindingandtargetgenetranscription
AT plemenitasana patientmutationinairedisruptsptefbbindingandtargetgenetranscription
AT sakselakalle patientmutationinairedisruptsptefbbindingandtargetgenetranscription
AT peterlinbmatija patientmutationinairedisruptsptefbbindingandtargetgenetranscription