Bruton's Tyrosine Kinase Is a Toll/Interleukin-1 Receptor Domain-binding Protein That Participates in Nuclear Factor κB Activation by Toll-like Receptor 4

Abstract

The Tec family of protein tyrosine kinases, of which Bruton's tyrosine kinase (Btk) 1 is a prototypical member, is involved in a vast array of signaling pathways in cells of hematopoietic lineage. Btk is expressed in all hematopoietic cells except T lymphocytes and natural killer cells. It is critically important for B-cell development as well as mature B-cell activation and survival. It has also been shown to be important for IgEmediated activation of mast cells resulting in allergic reactions. Btk kinase activity and tyrosine phosphorylation have both been shown to increase upon cross-linking or stimulation of the B-cell receptor, the IgE receptor (Fc⑀RII), and a number of cytokine receptors such as those for IL-3, IL-5, IL-6, and IL-10, suggesting a general role for Btk in immune regulation (1-4). Whereas the molecular mechanisms by which the B-cell receptor regulates B-cell proliferation and survival are not well understood, Btk has recently been shown to lie downstream of the B-cell receptor on the pathway regulating activation of the key pro-inflammatory transcription factor NF B (5-8). The biological importance of the signaling function has been shown by naturally occurring loss of function mutations in Btk in human X-linked agammaglobulinemia and its murine counterpart, X-linked immunodeficiency (Xid). These diseases are characterized by a block in B-cell development and defects in B-cell signaling, and in X-linked agammaglobulinemia patients, mutations in Btk are associated associated with an increased frequency of bacterial infections in all organs (9). Studies in Xid mice have also shown reduced responses to LPS stimulation, with nitric oxide (NO) production decreased, and macrophage effector functions impaired (10 -12). This, coupled with the observation that responses to T-independent antigens are impaired in Xid mice, suggests a role for Btk in innate immune responses.Toll-like receptors (TLRs) have an essential function in both innate and adaptive immunity and have evolved to recognize, with high specificity, diverse microbial pathogens (13). TLR4, as the receptor for the Gram-negative bacterial product LPS, is the prototypical member of the family (numbered TLR1-10 in humans) of type I transmembrane receptors, which are characterized by an extracellular leucine-rich repeat domain and an intracellular Toll/IL-1 receptor (TIR) domain, responsible for signaling. Ligands for other family members (except TLR10) have been identified and include bacterial flagellin and unmethylated bacterial CpG motifs for TLR5 and TLR9, respectively; double-stranded RNA for TLR3; and the antiviral compound R-848 recognizing TLR7 and TLR8. Research into how these receptors signal has identified MyD88 and IL-1-receptorassociated kinases (IRAKs) as key proximal signaling components regulating activation of the pro-inflammatory transcription factor NF B in response to LPS (reviewed in Ref. 14). Important differences in the proteins recruited to the different TLR members have also been described. Both TLR2 (the receptor for...

Signaling by Toll-like Receptors 8 and 9 Requires Bruton's Tyrosine Kinase

“…The ability of Btk to associate with the TIR domain of TLR4 was also demonstrated (10). In addition, however, we found that Btk can interact with the TIR domains of TLR8 and TLR9.…”

“…and TLR9-In a previous study, we found that a yeast two-hybrid screen carried out to search for possible interaction partners for Btk isolated a cDNA encoding human TLR8 (10). It was found that Btk could also interact with the TIR domains of TLR4, TLR6, and TLR9.…”

“…It was found that Btk could also interact with the TIR domains of TLR4, TLR6, and TLR9. However, the strongest interaction was found with the TIR domain of TLR8 (10). To confirm this interaction, we first carried out co-immunoprecipitation analysis.…”

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

“…The lyn -/-btk low mice do not develop autoAb or disease but still have B cells that are hyperresponsive to BCR ligation in terms of calcium flux, MAPK activation and proliferation [48]. Btk and Lyn are both involved in proinflammatory signaling pathways downstream of the BCR and IL-5R [49][50][51][52], thus overlap in function may also occur downstream of the conserved TIR domain of TLR4, TLR6, TLR8 and TLR9, a pathway known to involve Btk [53].…”

MicroRNAs in the regulation of TLR and RIG-I pathways

“…Many molecules have been identified as positive or negative regulators of TLR signaling, 6,7 including phosphatases (SHP-1, SHP-2, SHIP-1, PTP1B, [8][9][10][11] etc. ), protein kinases (calmodulin-dependent protein kinase II, Btk, MEKK3, [12][13][14] etc. ), ubiquitin-related proteins (A20, Nrdp1, CHIP, [15][16][17] etc.…”