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

Yu-San Huoh, Bin Wu, Sehoon Park, Darren Yang, Kushagra Bansal, Emily Greenwald, Wesley P. Wong, Diane Mathis and Sun Hur ()
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Yu-San Huoh: Department of Biological Chemistry and Molecular Pharmacology Blavatnik Institute at Harvard Medical School
Bin Wu: Department of Biological Chemistry and Molecular Pharmacology Blavatnik Institute at Harvard Medical School
Sehoon Park: Program in Cellular and Molecular Medicine Boston Children’s Hospital
Darren Yang: Department of Biological Chemistry and Molecular Pharmacology Blavatnik Institute at Harvard Medical School
Kushagra Bansal: Department of Immunology Blavatnik Institute at Harvard Medical School
Emily Greenwald: Program in Cellular and Molecular Medicine Boston Children’s Hospital
Wesley P. Wong: Department of Biological Chemistry and Molecular Pharmacology Blavatnik Institute at Harvard Medical School
Diane Mathis: Department of Immunology Blavatnik Institute at Harvard Medical School
Sun Hur: Department of Biological Chemistry and Molecular Pharmacology Blavatnik Institute at Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15448-w

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