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

doi:10.1101/2020.02.26.966424

Cited by 3 publications

(13 citation statements)

References 76 publications

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“…Corroborating with these experiments, mutations that disrupt DDF multimerization provide the molecular mechanisms for certain human diseases; for example, autoimmune polyendocrinopathy syndrome type 1 (APS-1) can be caused by mutations in Aire CARD that disrupt Aire polymerization [12].…”

Section: Functions and Regulation Of Ddf Filament Formationmentioning

confidence: 99%

“…Mutations that disrupt DDF filament formation in vitro have been shown to also cause the loss of ASC-mediated inflammasome formation, down regulation of RIP2-mediated inflammatory signaling, MAVS-stimulated antiviral signaling and Aire-mediated transcriptional activity [12,[24][25][26][27].…”

Section: Functions and Regulation Of Ddf Filament Formationmentioning

confidence: 99%

“…While certain DDFs in isolation show filament-like fibril structures upon overexpression [28][29][30], endogenous DDF-containing proteins instead display round foci or punctate structures. Additionally, in some cases, fusing DDF-protein with a bulky fluorescent tag altered the shape of filaments and other properties of the foci [12,19,31], demanding caution and carefully controlled experiments for visualization of DDF assemblies within cells. That being said, multiple immunofluorescence microscopy studies suggest that puncta formation of DDFcontaining proteins is likely mediated by filament formation.…”

Section: Ddf Filament Vs Foci Formationmentioning

confidence: 99%

“…Filamentous DDF assemblies have been well-studied in the context of various vertebrate immune processes including foreign nucleic acid sensing, inflammation, cell death and immune cell activation [2,9,10]. More recently, DDF proteins have been shown to also mediate transcriptional regulation of immune processes [11][12][13]. However, the functions of DDF-multimerization within the nucleus is only beginning to be realized.…”

Section: Introductionmentioning

confidence: 99%

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Death domain fold proteins in immune signaling and transcriptional regulation

Huoh

Hur

2021

The FEBS Journal

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Death Domain Fold (DDF) superfamily comprises of the death domain (DD), death effector domain (DED), caspase activation recruitment domain (CARD) and pyrin domain (PYD). By utilizing a conserved mode of interaction involving six distinct surfaces, a DDF serves as a building block that can densely pack into homo-multimers or filaments. Studies of immune signaling components have revealed that DDF-mediated filament formation plays a central role in mediating signal transduction and amplification. The unique ability of DDFs to self-oligomerize upon external Accepted ArticleThis article is protected by copyright. All rights reserved signals and induce oligomerization of partner molecules underlies key processes in many innate immune signaling pathways, as exemplified by RIG-I-like receptor signalosome and inflammasome assembly. Recent studies showed that DDFs are not limited to immune signaling pathways, but also are involved with transcriptional regulation and other biological processes. Considering that DDF annotation still remains a challenge, the current list of DDFs and their functions may represent just the tip of the iceberg within the full spectrum of DDF biology. In this review, we discuss recent advances in our understanding of DDF functions, structures and assembly architectures with a focus on CARDand PYD-containing proteins. We also discuss areas of future research and the potential relationship of DDFs with biomolecular condensates formed by liquid-liquid phase separation (LLPS).

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Section: Functions and Regulation Of Ddf Filament Formationmentioning

confidence: 99%

Section: Functions and Regulation Of Ddf Filament Formationmentioning

confidence: 99%

Section: Ddf Filament Vs Foci Formationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Death domain fold proteins in immune signaling and transcriptional regulation

Huoh

Hur

2021

The FEBS Journal

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“…Promiscuous expression of TRA is promoted by AIRE binding and inhibition of molecules that normally repress gene expression. These targets include a repressive complex of ATF7ip (activating transcription factor 7-interacting protein) and MBD1 (methyl CpGbinding protein), and hypomethylated lysine 4 of histone H3 (H3K4me0) [83][84][85][86][87][88]. The mechanism and structural basis for transactivation of TRA by AIRE are still under active investigation.…”

Section: The Thymic Medulla In Ttreg Development and Selectionmentioning

confidence: 99%

Thymic origins of autoimmunity—lessons from inborn errors of immunity

Bacchetta

Weinberg

2021

Semin Immunopathol

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During their intrathymic development, nascent T cells are empowered to protect against pathogens and to be operative for a life-long acceptance of self. While autoreactive effector T (Teff) cell progenitors are eliminated by clonal deletion, the intrathymic mechanisms by which thymic regulatory T cell (tTreg) progenitors maintain specificity for self-antigens but escape deletion to exert their regulatory functions are less well understood. Both tTreg and Teff development and selection result from finely coordinated interactions between their clonotypic T cell receptors (TCR) and peptide/MHC complexes expressed by antigen-presenting cells, such as thymic epithelial cells and thymic dendritic cells. tTreg function is dependent on expression of the FOXP3 transcription factor, and induction of FOXP3 gene expression by tTreg occurs during their thymic development, particularly within the thymic medulla. While initial expression of FOXP3 is downstream of TCR activation, constitutive expression is fixed by interactions with various transcription factors that are regulated by other extracellular signals like TCR and cytokines, leading to epigenetic modification of the FOXP3 gene. Most of the understanding of the molecular events underlying tTreg generation is based on studies of murine models, whereas gaining similar insight in the human system has been very challenging. In this review, we will elucidate how inborn errors of immunity illuminate the critical non-redundant roles of certain molecules during tTreg development, shedding light on how their abnormal development and function cause well-defined diseases that manifest with autoimmunity alone or are associated with states of immune deficiency and autoinflammation.

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Identification of topoisomerase as a precision-medicine target in chromatin reader SP140-driven Crohn’s disease

Amatullah

Digumarthi

Fraschilla

et al. 2021

Preprint

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How mis-regulated chromatin directly impacts human immunological disease is poorly understood. Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containing chromatin reader whose loss-of-function associates with Crohns disease (CD), multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL). However, mechanisms underlying SP140-driven pathogenicity and therapeutic approaches that rescue SP140 remain unexplored. Using a global proteomic strategy, we identified SP140 as a repressor of topoisomerases (TOP) that maintains heterochromatin and immune cell fate. In humans and mice, SP140 loss resulted in unleashed TOP activity, genome instability, severely compromised lineage-defining and microbe-inducible innate transcriptional programs and defective bacterial killing. Pharmacological inhibition of TOP1 or TOP2 rescued these defects. Furthermore, exacerbated colitis was restored with TOP1 or TOP2 inhibitors in Sp140-/- mice, but not wild-type mice, in vivo. Collectively, we identify SP140 as a repressor of topoisomerases and reveal repurposing of TOP inhibition as a precision strategy for reversing SP140-driven immune disease.

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

Cited by 3 publications

References 76 publications

Death domain fold proteins in immune signaling and transcriptional regulation

Death domain fold proteins in immune signaling and transcriptional regulation

Thymic origins of autoimmunity—lessons from inborn errors of immunity

Identification of topoisomerase as a precision-medicine target in chromatin reader SP140-driven Crohn’s disease

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