2. Academic Validation
  3. Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance

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

  • Nat Commun. 2020 Apr 2;11(1):1625. doi: 10.1038/s41467-020-15448-w.
Yu-San Huoh 1 2,  Bin Wu 1 2 3,  Sehoon Park 2,  Darren Yang 1 2 4,  Kushagra Bansal 5 6,  Emily Greenwald 2,  Wesley P Wong 1 2 4,  Diane Mathis 5,  Sun Hur 7 8
Affiliations

Affiliations

  • 1 Department of Biological Chemistry and Molecular Pharmacology Blavatnik Institute at Harvard Medical School, Boston, MA, 02115, USA.
  • 2 Program in Cellular and Molecular Medicine Boston Children's Hospital, Boston, MA, 02115, USA.
  • 3 NTU Institute of Structural Biology, School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore.
  • 4 Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.
  • 5 Department of Immunology Blavatnik Institute at Harvard Medical School, Boston, MA, 02115, USA.
  • 6 Molecular Biology & Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 560 064, India.
  • 7 Department of Biological Chemistry and Molecular Pharmacology Blavatnik Institute at Harvard Medical School, Boston, MA, 02115, USA. Sun.Hur@crystal.harvard.edu.
  • 8 Program in Cellular and Molecular Medicine Boston Children's Hospital, Boston, MA, 02115, USA. Sun.Hur@crystal.harvard.edu.
PMID: 32242017 DOI: 10.1038/s41467-020-15448-w
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.

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