Available online 9 September 2022, 104603
Highlights•BAFF 3-mer, BAFF 60-mer, and higher order multimers are present in human plasma.
•Compared to the BAFF 3-mer, BAFF 60-mer strongly induces the transcriptome of B cells.
•BAFF 60-mer is critical for classical NF-κB signaling and glucose oxidation.
•BAFF 60-mer-induced classical NF-κB signaling drives glucose oxidation.
•BR3 binding site on BAFF is critical BAFF 60-mer-induced B cell hyperactivation.
AbstractHuman recombinant B cell activating factor (BAFF) is secreted as 3-mers, which can associate to form 60-mers in culture supernatants. However, the presence of BAFF multimers in humans is still debated and it is incompletely understood how BAFF multimers activate the B cells. Here, we demonstrate that BAFF can exist as 60-mers or higher order multimers in human plasma. In vitro, BAFF 60-mer strongly induced the transcriptome of B cells which was partly attenuated by antagonism using a soluble fragment of BAFF receptor 3. Furthermore, compared to BAFF 3-mer, BAFF 60-mer strongly induced a transient classical and prolonged alternate NF-κB signaling, glucose oxidation by both aerobic glycolysis and oxidative phosphorylation, and succinate utilization by mitochondria. BAFF antagonism selectively attenuated classical NF-κB signaling and glucose oxidation. Altogether, our results suggest critical roles of BAFF 60-mer and its BAFF receptor 3 binding site in hyperactivation of B cells.
KeywordsBAFF multimers
B cell activation
Transcriptomics
NF-κB signaling
Metabolic reprogramming
AbbreviationsBAFFB cell activating Factor
BR3BAFF receptor 3, BAFF-R
TACITransmembrane activator and CAML interactor
BCMAB-cell maturation antigen
mBaffR-FcMurine BR3 ecto-domain fused to murine IgG1 Fc fragment, blocks BR3 binding site on BAFF
NF-κBNuclear factor kappa-light-chain-enhancer of activated B cells
IKKαInhibitor of NF-κB kinase α
IKKβInhibitor of NF-κB kinase β
SECSize exclusion chromatography
FPKMFragments Per Kilobase of transcript sequence per Millions base pairs sequenced
IPAIngenuity Pathway Analysis
OXPHOSOxidative phosphorylation
OCROxygen consumption rate
ECARExtracellular acidification rate
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