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Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance

Aggregate-like biomolecular assemblies are emerging as new conformational states with functionality. Aire, a transcription factor essential for central T cell tolerance, forms large aggregate-like assemblies visualized as nuclear foci. Here we demonstrate that Aire utilizes its caspase activation re...

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Autores principales: Huoh, Yu-San, Wu, Bin, Park, Sehoon, Yang, Darren, Bansal, Kushagra, Greenwald, Emily, Wong, Wesley P., Mathis, Diane, Hur, Sun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118133/
https://www.ncbi.nlm.nih.gov/pubmed/32242017
http://dx.doi.org/10.1038/s41467-020-15448-w
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author Huoh, Yu-San
Wu, Bin
Park, Sehoon
Yang, Darren
Bansal, Kushagra
Greenwald, Emily
Wong, Wesley P.
Mathis, Diane
Hur, Sun
author_facet Huoh, Yu-San
Wu, Bin
Park, Sehoon
Yang, Darren
Bansal, Kushagra
Greenwald, Emily
Wong, Wesley P.
Mathis, Diane
Hur, Sun
author_sort Huoh, Yu-San
collection PubMed
description Aggregate-like biomolecular assemblies are emerging as new conformational states with functionality. Aire, a transcription factor essential for central T cell tolerance, forms large aggregate-like assemblies visualized as nuclear foci. Here we demonstrate that Aire utilizes its caspase activation recruitment domain (CARD) to form filamentous homo-multimers in vitro, and this assembly mediates foci formation and transcriptional activity. However, CARD-mediated multimerization also makes Aire susceptible to interaction with promyelocytic leukemia protein (PML) bodies, sites of many nuclear processes including protein quality control of nuclear aggregates. Several loss-of-function Aire mutants, including those causing autoimmune polyendocrine syndrome type-1, form foci with increased PML body association. Directing Aire to PML bodies impairs the transcriptional activity of Aire, while dispersing PML bodies with a viral antagonist restores this activity. Our study thus reveals a new regulatory role of PML bodies in Aire function, and highlights the interplay between nuclear aggregate-like assemblies and PML-mediated protein quality control.
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spelling pubmed-71181332020-04-06 Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance Huoh, Yu-San Wu, Bin Park, Sehoon Yang, Darren Bansal, Kushagra Greenwald, Emily Wong, Wesley P. Mathis, Diane Hur, Sun Nat Commun Article Aggregate-like biomolecular assemblies are emerging as new conformational states with functionality. Aire, a transcription factor essential for central T cell tolerance, forms large aggregate-like assemblies visualized as nuclear foci. Here we demonstrate that Aire utilizes its caspase activation recruitment domain (CARD) to form filamentous homo-multimers in vitro, and this assembly mediates foci formation and transcriptional activity. However, CARD-mediated multimerization also makes Aire susceptible to interaction with promyelocytic leukemia protein (PML) bodies, sites of many nuclear processes including protein quality control of nuclear aggregates. Several loss-of-function Aire mutants, including those causing autoimmune polyendocrine syndrome type-1, form foci with increased PML body association. Directing Aire to PML bodies impairs the transcriptional activity of Aire, while dispersing PML bodies with a viral antagonist restores this activity. Our study thus reveals a new regulatory role of PML bodies in Aire function, and highlights the interplay between nuclear aggregate-like assemblies and PML-mediated protein quality control. Nature Publishing Group UK 2020-04-02 /pmc/articles/PMC7118133/ /pubmed/32242017 http://dx.doi.org/10.1038/s41467-020-15448-w Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Huoh, Yu-San
Wu, Bin
Park, Sehoon
Yang, Darren
Bansal, Kushagra
Greenwald, Emily
Wong, Wesley P.
Mathis, Diane
Hur, Sun
Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance
title Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance
title_full Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance
title_fullStr Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance
title_full_unstemmed Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance
title_short Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance
title_sort dual functions of aire card multimerization in the transcriptional regulation of t cell tolerance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118133/
https://www.ncbi.nlm.nih.gov/pubmed/32242017
http://dx.doi.org/10.1038/s41467-020-15448-w
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