Abstract
BackgroundThe B cell antigen receptor (BCR) and pathogen recognition receptors, such as Toll-like receptor 4 (TLR4), act in concert to control adaptive B cell responses. However, little is known about the signaling pathways that integrate BCR activation with intrinsic TLR4 stimulation. Antigen receptors initialize activation of the inducible transcription factor nuclear factor-κB (NF-κB) via recruitment of the membrane-associated guanylate kinase caspase recruitment domain protein 11 (CARD11), the adapter molecule B cell CLL/lymphoma 10 (BCL10), and the "paracaspase" mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) into lipid rafts. Upon BCR triggering, this activation strictly depends on BCL10, but not on MALT1, leading to the hypothesis that a MALT1-independent NF-κB activation pathway contributes to BCR-induced NF-κB activation downstream of BCL10. The identity of this pathway has remained elusive.ResultsUsing genetic and biochemical approaches, we demonstrate that the IRAK4- and IRAK1-dependent TLR signaling branch is activated upon BCR triggering to induce partial NF-κB activation. BCR-induced MALT1-independent IκB degradation and B cell proliferation were inhibited in MALT1/IRAK4 double knockout B cells. Moreover, IRAK1 was recruited into lipid rafts upon BCR stimulation and activated following transient recruitment of IRAK4.ConclusionWe propose that the observed crosstalk between BCR and TLR signaling components may contribute to the discrimination of signals that emanate from single and dual receptor engagement to control adaptive B cell responses.
Highlights
The B cell antigen receptor (BCR) and pathogen recognition receptors, such as Toll-like receptor 4 (TLR4), act in concert to control adaptive B cell responses
Our results demonstrate that mediators of the TLR4 signaling pathway to nuclear factor-B (NF-B) are engaged upon BCR activation to contribute to B cell proliferation
mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) and interleukin receptor-associated kinase 4 (IRAK4) independently mediate antigen receptor-induced B cell proliferation To reassess the role of MALT1 in B cell activation, we purified splenic B cells from MALT1+/- and MALT1-/mice and stimulated them with anti-IgM antibodies, or anti-IgM plus anti-CD40, or LPS
Summary
The B cell antigen receptor (BCR) and pathogen recognition receptors, such as Toll-like receptor 4 (TLR4), act in concert to control adaptive B cell responses. Upon BCR triggering, this activation strictly depends on BCL10, but not on MALT1, leading to the hypothesis that a MALT1-independent NF-B activation pathway contributes to BCR-induced NF-B activation downstream of BCL10. BCL10 and MALT1 mediate activation of the IKK complex that induces degradation of IB proteins, the inhibitors of NF-B that retain it in the cytoplasm, which leads to the activation of NF-B [9] This process requires lysine 63-linked polyubiquitination events that involve the E3-ligase tumor necrosis factor receptor-associated factor 6 (TRAF6) and mediate complex formation between components of the CBM complex, TRAF6, transforming growth factor b-activated kinase 1 (TAK1) and the IKK complex [10,11,12,13]
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