Figure 2.
Model illustrating the molecular consequences of the three forms of AD inborn errors of NF-κB2 in mTECs. In the basal state, the NF-κB2 precursor p100 acts as a transcriptional inhibitor by forming cytoplasmic homomultimeric complexes. These complexes, known as “kappaBsomes,” bind p52 and RelB, restricting their transcriptional activity (referred to as the “IκBδ function” of p100). When the alternative NF-κB pathway is triggered by upstream TNF receptors (presumably RANK and/or CD40), the C-terminal part of the p100 precursor is processed into the proteasome to generate p52, the transcriptionally active form of NF-κB2, which dimerizes with RelB to form p52/RelB heterodimers. After translocation to the nucleus, this heterodimer binds to κB sites to regulate the transcription of targeted genes controlling mTEC development and functions, including AIRE. The p52GOF/IκBδLOF alleles are transcriptionally active but lack IκBδ function, leading to spontaneous nuclear translocation. In the heterozygous state, WT-p52 and mutant-p52 (if expressed) form normal or increased levels of transcriptionally active p52-containing homo- or heterodimers, leading to enhanced p52-dependent transcription. p52LOF/IκBδLOF alleles are non-functional for both p52 and IκBδ activities. In heterozygous cells (p52 haploinsufficiency), the pool of WT-p52– and RelB-dependent dimers is maintained at near-normal levels by transcriptional regulation and remains sufficient to support normal AIRE transcription and function. By contrast, p52LOF/IκBδGOF alleles are resistant to processing, resulting in a combination of impaired p52 generation, and high levels of IκBδ-dependent inhibitory activity of the mutant p100 against RelB and WT-p52. The amounts of WT-p52– and RelB-dependent dimers are markedly decreased, preventing sufficient AIRE-dependent central T cell tolerance to type I IFNs and leading to the development of AAN-I-IFNs. “p52 TA” reflects the level of p52-dependent transcriptional activity (TA), whether mediated by homodimers or heterodimers. For simplicity, only p52- homodimers or p52/RelB-containing dimers are represented. The expression of the proteins encoded by the p52GOF/IκBδLOF alleles has not been documented in patients’ cells.

Model illustrating the molecular consequences of the three forms of AD inborn errors of NF-κB2 in mTECs. In the basal state, the NF-κB2 precursor p100 acts as a transcriptional inhibitor by forming cytoplasmic homomultimeric complexes. These complexes, known as “kappaBsomes,” bind p52 and RelB, restricting their transcriptional activity (referred to as the “IκBδ function” of p100). When the alternative NF-κB pathway is triggered by upstream TNF receptors (presumably RANK and/or CD40), the C-terminal part of the p100 precursor is processed into the proteasome to generate p52, the transcriptionally active form of NF-κB2, which dimerizes with RelB to form p52/RelB heterodimers. After translocation to the nucleus, this heterodimer binds to κB sites to regulate the transcription of targeted genes controlling mTEC development and functions, including AIRE. The p52GOF/IκBδLOF alleles are transcriptionally active but lack IκBδ function, leading to spontaneous nuclear translocation. In the heterozygous state, WT-p52 and mutant-p52 (if expressed) form normal or increased levels of transcriptionally active p52-containing homo- or heterodimers, leading to enhanced p52-dependent transcription. p52LOF/IκBδLOF alleles are non-functional for both p52 and IκBδ activities. In heterozygous cells (p52 haploinsufficiency), the pool of WT-p52– and RelB-dependent dimers is maintained at near-normal levels by transcriptional regulation and remains sufficient to support normal AIRE transcription and function. By contrast, p52LOF/IκBδGOF alleles are resistant to processing, resulting in a combination of impaired p52 generation, and high levels of IκBδ-dependent inhibitory activity of the mutant p100 against RelB and WT-p52. The amounts of WT-p52– and RelB-dependent dimers are markedly decreased, preventing sufficient AIRE-dependent central T cell tolerance to type I IFNs and leading to the development of AAN-I-IFNs. “p52 TA” reflects the level of p52-dependent transcriptional activity (TA), whether mediated by homodimers or heterodimers. For simplicity, only p52- homodimers or p52/RelB-containing dimers are represented. The expression of the proteins encoded by the p52GOF/IκBδLOF alleles has not been documented in patients’ cells.

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