MyD88 Adapter-like (Mal) Is Phosphorylated by Bruton's Tyrosine Kinase during TLR2 and TLR4 Signal Transduction

Gray, Pearl; Dunne, Aisling; Brikos, Constantinos; Jefferies, Caroline A.; Doyle, Sarah; O’Neill, Luke A. J.

doi:10.1074/jbc.m508892200

Cited by 183 publications

(120 citation statements)

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“…For instance, myristoylation and serine phosphorylation of TRAM is important for its membrane anchoring and signaling (56,57). LPS triggers tyrosine phosphorylation of MyD88 (60), and tyrosine phosphorylation of Mal has been reported to be important for TLR2 and TLR4 signaling (55). Non-classical Lys-63 ubiquitination of TRAF-6, necessary for induction of its functional activities, is another example of posttranslational modifications of adapters (61).…”

Section: Discussionmentioning

confidence: 99%

“…pEFBOS-His/ FLAG-human MD-2 was provided by Dr. Kensuke Miyake (Research Institute for Microbial Diseases, Osaka University, Osaka, Japan). pEFBOS-FLAG-Mal WT and P125H mutant, pDC304-HA-Mal, pCDNA3-YFP-MyD88, pCDNA3-Btk, pCDNA3-Myc-IRAK-2, and pRK5-FLAG-TRAF-6 were described previously (27,51,55). pFLAG-CMV-1 encoding WT CD4-TLR4 was kindly provided by Dr. Stephen T. Smale (Howard Hughes Medical Institute, UCLA, Los Angeles, CA), and pRL-TK-Renilla luciferase was from Promega.…”

Section: Methodsmentioning

confidence: 99%

“…TLR2, TLR3, TLR4, and TLR5 undergo agonist-induced tyrosine phosphorylation, and mutations of tyrosines within their TIR domains suppress TLR signaling capacities (51)(52)(53)(54) and alter recruitment of MyD88 to TLR4 and IRAK-1 activation at TLR4 (51). Tyrosine phosphorylation of Mal and serine phosphorylation and myristoylation of TRIF were found to regulate TLR signaling (55)(56)(57). For instance, Mal is tyrosine-phosphorylated by Bruton tyrosine kinase (Btk), and mutations of Tyr-86 or Tyr-106 render Mal functionally incompetent and confer upon it the capacity to act as a dominant negative inhibitor of LPS-mediated NF-B reporter activation (55).…”

mentioning

confidence: 99%

“…Tyrosine phosphorylation of Mal and serine phosphorylation and myristoylation of TRIF were found to regulate TLR signaling (55)(56)(57). For instance, Mal is tyrosine-phosphorylated by Bruton tyrosine kinase (Btk), and mutations of Tyr-86 or Tyr-106 render Mal functionally incompetent and confer upon it the capacity to act as a dominant negative inhibitor of LPS-mediated NF-B reporter activation (55). However, functional significance of Mal tyrosine phosphorylation in activation of endogenous signaling intermediates was not characterized.…”

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confidence: 99%

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Tyrosine Phosphorylation of MyD88 Adapter-like (Mal) Is Critical for Signal Transduction and Blocked in Endotoxin Tolerance

Piao

Song

Chen

et al. 2008

Journal of Biological Chemistry

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confidence: 99%

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Tyrosine Phosphorylation of MyD88 Adapter-like (Mal) Is Critical for Signal Transduction and Blocked in Endotoxin Tolerance

Piao

Song

Chen

et al. 2008

Journal of Biological Chemistry

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“…Recent studies have suggested a linkage of TLRs and tyrosine kinases, including Syk via MyD88-STAP-2 interaction (51) and Btk via direct interaction with TIR domain (52), both of which have been shown to activate PLC␥ isoforms. Moreover, Btkinduced phosphorylation of TIRAP/Mal has recently been reported to play an important role in TLR signal transduction (53), which may occur at a phosphatidylinositol diphosphaterich membrane compartment after recruitment of MyD88 to membrane-localized TIRAP/Mal (54). A schematic of signaling pathways proposed here is shown in Fig.…”

Section: Volume 282 • Number 11 • March 16 2007mentioning

confidence: 99%

Pathogen Recognition by Toll-like Receptor 2 Activates Weibel-Palade Body Exocytosis in Human Aortic Endothelial Cells

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Kanno

Dohkan

et al. 2007

Journal of Biological Chemistry

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The endothelial cell-specific granule Weibel-Palade body releases vasoactive substances capable of modulating vascular inflammation. Although innate recognition of pathogens by Toll-like receptors (TLRs) is thought to play a crucial role in promotion of inflammatory responses, the molecular basis for early-phase responses of endothelial cells to bacterial pathogens has not fully been understood. We here report that human aortic endothelial cells respond to bacterial lipoteichoic acid (LTA) and synthetic bacterial lipopeptides, but not lipopolysaccharide or peptidoglycan, to induce Weibel-Palade body exocytosis, accompanied by release or externalization of the storage components von Willebrand factor and P-selectin. LTA could activate rapid Weibel-Palade body exocytosis through a TLR2-and MyD88-dependent mechanism without de novo protein synthesis. This process was at least mediated through MyD88-dependent phosphorylation and activation of phospholipase C␥. Moreover, LTA activated interleukin-1 receptor-associated kinase-1-dependent delayed exocytosis with de novo protein synthesis and phospholipase C␥-dependent activation of the NF-B pathway. Increased TLR2 expression by transfection or interferon-␥ treatment increased TLR2-mediated Weibel-Palade body exocytosis, whereas reduced TLR2 expression under laminar flow decreased the response. Thus, we propose a novel role for TLR2 in induction of a primary proinflammatory event in aortic endothelial cells through Weibel-Palade body exocytosis, which may be an important step for linking innate recognition of bacterial pathogens to vascular inflammation.

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Targeting B Cells and Microglia in Multiple Sclerosis With Bruton Tyrosine Kinase Inhibitors

2023

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ImportanceCurrently, disease-modifying therapies for multiple sclerosis (MS) use 4 mechanisms of action: immune modulation, suppressing immune cell proliferation, inhibiting immune cell migration, or cellular depletion. Over the last decades, the repertoire substantially increased because of the conceptual progress that not only T cells but also B cells play an important pathogenic role in MS, fostered by the empirical success of B cell–depleting antibodies against the surface molecule CD20. Notwithstanding this advance, a continuous absence of B cells may harbor safety risks, such as a decline in the endogenous production of immunoglobulins. Accordingly, novel B cell–directed MS therapies are in development, such as inhibitors targeting Bruton tyrosine kinase (BTK).ObservationsBTK is centrally involved in the B cell receptor–mediated activation of B cells, one key requirement in the development of autoreactive B cells, but also in the activation of myeloid cells, such as macrophages and microglia. Various compounds in development differ in their binding mode, selectivity and specificity, relative inhibitory concentration, and potential to enter the central nervous system. The latter may be important in assessing whether BTK inhibition is a promising strategy to control inflammatory circuits within the brain, the key process that is assumed to drive MS progression. Accordingly, clinical trials using BTK inhibitors are currently conducted in patients with relapsing-remitting MS as well as progressive MS, so far generating encouraging data regarding efficacy and safety.Conclusions and RelevanceWhile the novel approach of targeting BTK is highly promising, several questions remain unanswered, such as the long-term effects of using BTK inhibitors in the treatment of inflammatory CNS disease. Potential changes in circulating antibody levels should be evaluated and compared with B cell depletion. Also important is the potential of BTK inhibitors to enter the CNS, which depends on the given compound. Remaining questions involve where BTK inhibitors fit in the landscape of MS therapeutics. A comparative analysis of their distinct properties is necessary to identify which inhibitors may be used in relapsing vs progressive forms of MS as well as to clarify which agent may be most suitable for sequential use after anti-CD20 treatment.

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MyD88 Adapter-like (Mal) Is Phosphorylated by Bruton's Tyrosine Kinase during TLR2 and TLR4 Signal Transduction

Abstract: Members of the

Cited by 183 publications

References 36 publications

Tyrosine Phosphorylation of MyD88 Adapter-like (Mal) Is Critical for Signal Transduction and Blocked in Endotoxin Tolerance

Tyrosine Phosphorylation of MyD88 Adapter-like (Mal) Is Critical for Signal Transduction and Blocked in Endotoxin Tolerance

Pathogen Recognition by Toll-like Receptor 2 Activates Weibel-Palade Body Exocytosis in Human Aortic Endothelial Cells

Targeting B Cells and Microglia in Multiple Sclerosis With Bruton Tyrosine Kinase Inhibitors

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