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Signaling flux redistribution at toll-like receptor pathway junctions.

Selvarajoo K, Takada Y, Gohda J, Helmy M, Akira S, Tomita M, Tsuchiya M, Inoue J, Matsuo K - PLoS ONE (2008)

Bottom Line: Furthermore, increasing the amount of MyD88 in cultured cells showed decreased TRAM binding to TLR4.Investigating another TLR4 pathway junction, from TRIF to TRAF6, RIP1 and TBK1, the removal of MyD88-dependent TRAF6 increased expression of TRAM-dependent Cxcl10 and Ifit2.Thus, we demonstrate that SFR is a novel mechanism for enhanced activation of alternative pathways when molecules at pathway junctions are removed.

View Article: PubMed Central - PubMed

Affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan. kumar@ttck.keio.ac.jp

ABSTRACT
Various receptors on cell surface recognize specific extracellular molecules and trigger signal transduction altering gene expression in the nucleus. Gain or loss-of-function mutations of one molecule have shown to affect alternative signaling pathways with a poorly understood mechanism. In Toll-like receptor (TLR) 4 signaling, which branches into MyD88- and TRAM-dependent pathways upon lipopolysaccharide (LPS) stimulation, we investigated the gain or loss-of-function mutations of MyD88. We predict, using a computational model built on the perturbation-response approach and the law of mass conservation, that removal and addition of MyD88 in TLR4 activation, enhances and impairs, respectively, the alternative TRAM-dependent pathway through signaling flux redistribution (SFR) at pathway branches. To verify SFR, we treated MyD88-deficient macrophages with LPS and observed enhancement of TRAM-dependent pathway based on increased IRF3 phosphorylation and induction of Cxcl10 and Ifit2. Furthermore, increasing the amount of MyD88 in cultured cells showed decreased TRAM binding to TLR4. Investigating another TLR4 pathway junction, from TRIF to TRAF6, RIP1 and TBK1, the removal of MyD88-dependent TRAF6 increased expression of TRAM-dependent Cxcl10 and Ifit2. Thus, we demonstrate that SFR is a novel mechanism for enhanced activation of alternative pathways when molecules at pathway junctions are removed. Our data suggest that SFR may enlighten hitherto unexplainable intracellular signaling alterations in genetic diseases where gain or loss-of-function mutations are observed.

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Schematic representation of Signaling Flux Redistribution (SFR).(A) removal of MyD88 results in enhancement of TRAM-dependant pathway, (B) removal of TRAF6 results in enhancement of TRAM-dependant pathway downstream of TRIF, (C) overexpression of MyD88 downregulates TRAM-dependant pathway, (D) removal of TRAM does not enhance the MyD88-dependant pathway due to upstream intermediates. * signaling molecules/events upstream of TRAM [9], [25], [26].
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pone-0003430-g005: Schematic representation of Signaling Flux Redistribution (SFR).(A) removal of MyD88 results in enhancement of TRAM-dependant pathway, (B) removal of TRAF6 results in enhancement of TRAM-dependant pathway downstream of TRIF, (C) overexpression of MyD88 downregulates TRAM-dependant pathway, (D) removal of TRAM does not enhance the MyD88-dependant pathway due to upstream intermediates. * signaling molecules/events upstream of TRAM [9], [25], [26].

Mentions: Since cells are able to execute numerous processes using only a limited set of interaction domains that have flexible binding properties [23], we believe SFR at these domains can enhance or impair alternative pathways when a competing molecule such as MyD88 or TRAF6 is removed (Figure 5A,B) or increased (Figure 5C). In addition to TRAF6 and TBK1, RIP1 and RIP3 also compete for TRIF, and binding of RIP3 to TRIF is increased in the absence of RIP1 [24]. SFR predicts the enhanced activation of the RIP3-dependent pathway in RIP1-deficient cells.


Signaling flux redistribution at toll-like receptor pathway junctions.

Selvarajoo K, Takada Y, Gohda J, Helmy M, Akira S, Tomita M, Tsuchiya M, Inoue J, Matsuo K - PLoS ONE (2008)

Schematic representation of Signaling Flux Redistribution (SFR).(A) removal of MyD88 results in enhancement of TRAM-dependant pathway, (B) removal of TRAF6 results in enhancement of TRAM-dependant pathway downstream of TRIF, (C) overexpression of MyD88 downregulates TRAM-dependant pathway, (D) removal of TRAM does not enhance the MyD88-dependant pathway due to upstream intermediates. * signaling molecules/events upstream of TRAM [9], [25], [26].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2561291&req=5

pone-0003430-g005: Schematic representation of Signaling Flux Redistribution (SFR).(A) removal of MyD88 results in enhancement of TRAM-dependant pathway, (B) removal of TRAF6 results in enhancement of TRAM-dependant pathway downstream of TRIF, (C) overexpression of MyD88 downregulates TRAM-dependant pathway, (D) removal of TRAM does not enhance the MyD88-dependant pathway due to upstream intermediates. * signaling molecules/events upstream of TRAM [9], [25], [26].
Mentions: Since cells are able to execute numerous processes using only a limited set of interaction domains that have flexible binding properties [23], we believe SFR at these domains can enhance or impair alternative pathways when a competing molecule such as MyD88 or TRAF6 is removed (Figure 5A,B) or increased (Figure 5C). In addition to TRAF6 and TBK1, RIP1 and RIP3 also compete for TRIF, and binding of RIP3 to TRIF is increased in the absence of RIP1 [24]. SFR predicts the enhanced activation of the RIP3-dependent pathway in RIP1-deficient cells.

Bottom Line: Furthermore, increasing the amount of MyD88 in cultured cells showed decreased TRAM binding to TLR4.Investigating another TLR4 pathway junction, from TRIF to TRAF6, RIP1 and TBK1, the removal of MyD88-dependent TRAF6 increased expression of TRAM-dependent Cxcl10 and Ifit2.Thus, we demonstrate that SFR is a novel mechanism for enhanced activation of alternative pathways when molecules at pathway junctions are removed.

View Article: PubMed Central - PubMed

Affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan. kumar@ttck.keio.ac.jp

ABSTRACT
Various receptors on cell surface recognize specific extracellular molecules and trigger signal transduction altering gene expression in the nucleus. Gain or loss-of-function mutations of one molecule have shown to affect alternative signaling pathways with a poorly understood mechanism. In Toll-like receptor (TLR) 4 signaling, which branches into MyD88- and TRAM-dependent pathways upon lipopolysaccharide (LPS) stimulation, we investigated the gain or loss-of-function mutations of MyD88. We predict, using a computational model built on the perturbation-response approach and the law of mass conservation, that removal and addition of MyD88 in TLR4 activation, enhances and impairs, respectively, the alternative TRAM-dependent pathway through signaling flux redistribution (SFR) at pathway branches. To verify SFR, we treated MyD88-deficient macrophages with LPS and observed enhancement of TRAM-dependent pathway based on increased IRF3 phosphorylation and induction of Cxcl10 and Ifit2. Furthermore, increasing the amount of MyD88 in cultured cells showed decreased TRAM binding to TLR4. Investigating another TLR4 pathway junction, from TRIF to TRAF6, RIP1 and TBK1, the removal of MyD88-dependent TRAF6 increased expression of TRAM-dependent Cxcl10 and Ifit2. Thus, we demonstrate that SFR is a novel mechanism for enhanced activation of alternative pathways when molecules at pathway junctions are removed. Our data suggest that SFR may enlighten hitherto unexplainable intracellular signaling alterations in genetic diseases where gain or loss-of-function mutations are observed.

Show MeSH
Related in: MedlinePlus