TRAF5
Overview
TRAF5 (TNF Receptor-Associated Factor 5) is an essential mediator of CD40 signalling and the main negative regulator of TLR signalling in mouse B cells. Its deficiency in DN2 and aNAV B cells provides the mechanistic basis for the dual phenotype of these cells: unresponsive to CD40L (signal 2) but hyper-responsive to TLR7 (signal 3).
Key Points from Literature
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Uniquely low in DN2 and aNAV: TRAF5 expression is lowest in DN2 and aNAV cells among all B cell subsets (RNA-seq). Also low: TNFAIP3 (A20, a major SLE susceptibility gene) and TRAF3IP2 — other regulators of TNF/TLR signalling pathways (see Jenks2018 - DN2 B Cells and EF Pathway in SLE).
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Functional consequence — CD40L unresponsiveness: CD40L stimulation increases CD25 expression in NAV cells but not in DN2 cells, consistent with defective CD40 signalling downstream of low TRAF5 (see Jenks2018 - DN2 B Cells and EF Pathway in SLE).
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Functional consequence — TLR7 hyper-responsiveness: Low TRAF5 removes negative regulation of TLR signalling. DN2 and aNAV cells show enhanced pERK and pMAPKp38 phosphorylation after R848 (TLR7 agonist) stimulation relative to all other B cell subsets (see Jenks2018 - DN2 B Cells and EF Pathway in SLE, phospho-flow n=5–10).
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ZEB1 binding motifs: Genes with low DN2 expression (including TRAF5, CXCR5, and CR2) are enriched for ZEB1 binding motifs, suggesting coordinated transcriptional downregulation (see Jenks2018 - DN2 B Cells and EF Pathway in SLE).
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TRAF5 deficiency contributes to enhanced TLR7 signalling: Low TRAF5 in DN2/aNAV cells may also contribute to enhanced TLR7 signalling beyond removing negative regulation — consistent with TRAF5’s dual role in mediating CD40 signalling and restraining TLR7 (see Sanz2025 - Human Atypical B Cells Overview, review).
Contradictions & Debates
None documented in current wiki sources.
Related Pages
TLR7, DN2 B Cell, Activated Naive B Cell, Extrafollicular Response