FBXO3 Protein Promotes Ubiquitylation and Transcriptional Activity of AIRE (Autoimmune Regulator)

Shao, Wei; Žumer, Kristina; Fujinaga, Koh; Peterlin, B. Matija

doi:10.1074/jbc.m116.724401

Cited by 20 publications

(22 citation statements)

References 47 publications

(40 reference statements)

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“…1f. We expressed Aire in human embryonic kidney 293 T cells and Aire-deficient human thymic epithelial 4D6 cells, two model cell lines that can recapitulate many aspects of Aire's function in mTECs, including transcriptional activity and interaction partners 13,20,25,35,36 . The transient expression conditions that we used closely emulate endogenous Aire's nuclear foci formation and the functional effects of patient mutations.…”

Section: Resultsmentioning

confidence: 99%

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

Huoh

Park

et al. 2020

Nat Commun

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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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Section: Resultsmentioning

confidence: 99%

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

Huoh

Park

et al. 2020

Nat Commun

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“…However, direct binding studies are difficult, as post-translational modifications direct interactions between these TFs and P-TEFb. They include phosphorylation, acetylation, and ubiquitylation (26,34,35). Nevertheless, co-immunoprecipitations revealed that interactions between AIRE or NF-B and P-TEFb are BRD4independent in cells.…”

Section: Discussionmentioning

confidence: 99%

Bromodomain-containing protein 4–independent transcriptional activation by autoimmune regulator (AIRE) and NF-κB

Huang

Shao

Fujinaga

et al. 2018

Journal of Biological Chemistry

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Autoimmune regulator (AIRE) and nuclear factor-κB (NF-κB) are transcription factors (TFs) that direct the expression of individual genes and gene clusters. Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator that recognizes and binds to acetylated histones. BRD4 also has been reported to promote interactions between the positive transcription elongation factor b (P-TEFb) and AIRE or P-TEFb and NF-κB subunit p65. Here, we report that AIRE and p65 bind to P-TEFb independently of BRD4. JQ1, a compound that disrupts interactions between BRD4 and acetylated proteins, does not decrease transcriptional activities of AIRE or p65. Moreover, siRNA-mediated inactivation of BRD4 alone or in combination with JQ1 had no effects on AIRE- and NF-κB-targeted genes on plasmids and in chromatin and on interactions between P-TEFb and AIRE or NF-κB. Finally, ChIP experiments revealed that recruitment of P-TEFb to AIRE or p65 to transcription complexes was independent of BRD4. We conclude that direct interactions between AIRE, NF-κB, and P-TEFb result in efficient transcription of their target genes.

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“…As such, direct visualization of the filament microstructure within the dense foci has been challenging. Thus, to understand how CARD filament formation mediates Aire foci formation and transcriptional activity, we examined the behavior of WT and Aire variants examined in Fig 1f. We expressed Aire in human embryonic kidney 293T cells and Aire-deficient human thymic epithelial 4D6 cells, two model cell lines that can recapitulate many aspects of Aire's function in mTECs, including transcriptional activity and interaction partners 13,20,25,35,36 . The transient expression conditions that we used closely emulate endogenous Aire's nuclear foci formation and the functional effects of patient mutations.…”

Section: Introductionmentioning

confidence: 99%

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

Huoh¹,

Wu²,

Park

et al. 2020

Preprint

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ABSTRACTAggregate-like biomolecular assemblies are emerging as new conformational states with functionality. Aire, a transcription factor essential for central T cell tolerance, is known to form large aggregate-like assemblies visualized as nuclear foci. We demonstrate that Aire utilizes 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 is a double-edged sword as it also makes Aire susceptible to interaction with 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 Aire’s transcriptional activity, while dispersing PML bodies with a viral antagonist restores it. Thus, our study reveals a new regulatory role of PML bodies in Aire function and highlights the interplay between nuclear aggregate-like assemblies and PML-mediated quality control.

show abstract

FBXO3 Protein Promotes Ubiquitylation and Transcriptional Activity of AIRE (Autoimmune Regulator)

Cited by 20 publications

References 47 publications

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

Bromodomain-containing protein 4–independent transcriptional activation by autoimmune regulator (AIRE) and NF-κB

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

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