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The Architecture of the TIR Domain Signalosome in the Toll-like Receptor-4 Signaling Pathway.

Guven-Maiorov E, Keskin O, Gursoy A, VanWaes C, Chen Z, Tsai CJ, Nussinov R - Sci Rep (2015)

Bottom Line: The architecture that we obtain with 8 MyD88 molecules provides the structural basis for the MyD88-templated myddosome helical assembly and receptor clustering; it also provides clues to pro- and anti-inflammatory signaling pathways branching at the signalosome level to Mal/MyD88 and TRAM/TRIF pro- and anti-inflammatory pathways.The assembly of MyD88 death domain (DD) with TRAF3 (anti-viral/anti-inflammatory) and TRAF6 (pro-inflammatory) suggest that TRAF3/TRAF6 binding sites on MyD88 DD partially overlap, as do IRAK4 and FADD.Significantly, the organization illuminates mechanisms of oncogenic mutations, demonstrates that almost all TLR4 parallel pathways are competitive and clarifies decisions at pathway branching points.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey.

ABSTRACT
Activated Toll-like receptors (TLRs) cluster in lipid rafts and induce pro- and anti-tumor responses. The organization of the assembly is critical to the understanding of how these key receptors control major signaling pathways in the cell. Although several models for individual interactions were proposed, the entire TIR-domain signalosome architecture has not been worked out, possibly due to its complexity. We employ a powerful algorithm, crystal structures and experimental data to model the TLR4 and its cluster. The architecture that we obtain with 8 MyD88 molecules provides the structural basis for the MyD88-templated myddosome helical assembly and receptor clustering; it also provides clues to pro- and anti-inflammatory signaling pathways branching at the signalosome level to Mal/MyD88 and TRAM/TRIF pro- and anti-inflammatory pathways. The assembly of MyD88 death domain (DD) with TRAF3 (anti-viral/anti-inflammatory) and TRAF6 (pro-inflammatory) suggest that TRAF3/TRAF6 binding sites on MyD88 DD partially overlap, as do IRAK4 and FADD. Significantly, the organization illuminates mechanisms of oncogenic mutations, demonstrates that almost all TLR4 parallel pathways are competitive and clarifies decisions at pathway branching points. The architectures are compatible with the currently-available experimental data and provide compelling insights into signaling in cancer and inflammation pathways.

No MeSH data available.


Related in: MedlinePlus

Toll-like receptor pathway (adapted from literature121519), in traditional node-and-edge representation, where nodes represent proteins and edges represent interactions between proteins.TLR pathway is complicated and has many branches. Stimulation of TLRs propagate the signal through two parallel paths: MyD88-dependent path (green), which leads to production of pro-inflammatory cytokines, and TRIF-dependent path (orange), which gives rise to transcription of antiviral proteins—interferons—and anti-inflammatory cytokine IL-10. MyD88-mediated pathway also has three branches, namely TRAF6- (green), TRAF3- (orange) (downstream of endosomal TLRs), and FADD-dependent (pink) downstream pathways. For space limitation, we showed TLRs on endosomal membrane as monomers, but they also dimerize upon stimulation.
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f1: Toll-like receptor pathway (adapted from literature121519), in traditional node-and-edge representation, where nodes represent proteins and edges represent interactions between proteins.TLR pathway is complicated and has many branches. Stimulation of TLRs propagate the signal through two parallel paths: MyD88-dependent path (green), which leads to production of pro-inflammatory cytokines, and TRIF-dependent path (orange), which gives rise to transcription of antiviral proteins—interferons—and anti-inflammatory cytokine IL-10. MyD88-mediated pathway also has three branches, namely TRAF6- (green), TRAF3- (orange) (downstream of endosomal TLRs), and FADD-dependent (pink) downstream pathways. For space limitation, we showed TLRs on endosomal membrane as monomers, but they also dimerize upon stimulation.

Mentions: Toll-like receptors (TLRs) orchestrate the innate and adaptive immune systems1. The TLR pathway (Fig. 1) plays critical roles in almost every phase of tumor development2. Two opposing roles are attributed to TLRs: anti-tumor and pro-tumor actions3. TLR-induced inflammation promotes cancer via proliferative and anti-apoptotic factors4. TLRs form homo- or hetero-dimers and their cytoplasmic Toll/IL-1R homology (TIR) domains associate with TIR domain-containing adaptor molecules to stimulate signaling5. They have six adaptor proteins, Myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like (Mal, also known as TIRAP)6, TIR domain containing adaptor inducing interferon-β (TRIF, also known as TICAM-1)7, TRIF-related adaptor molecule (TRAM, also known as TICAM-2)8, sterile α and heat-armadillo motifs (SARM)9, and B-cell adaptor for PI3K (BCAP)10. TLR signaling induces expression of pro-inflammatory cytokines, interferons (IFNs) and interleukin-10 (IL-10, an anti-inflammatory cytokine). While IFN production suppresses cancer, pro-inflammatory cytokines promote it11. Upon stimulation, TLRs cluster in lipid rafts1213. In their MyD88-dependent pathway, the TLR TIR domains associate with TIR domains of MyD88 and Mal proteins. MyD88 TIR domain is connected through a long linker to its DD. Through its DD, MyD88 can initiate three downstream pathways. In the first, pro-survival inflammatory pathway, it recruits serine/threonine kinases IRAKs (Interleukin-1 receptor-associated kinases) to stimulate the TNF receptor-associated factor 6 (TRAF6), IKK complex and MAPKs, (e.g. ERK, JNK, and p3814) and transcription factors NF-κB, AP-1, and CREB1516, which ultimately result in transcription of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), and IL-1β17. In the second path, MyD88 DD binds to TRAF3 instead of TRAF6 (only TLRs on endosomal membranes recruit TRAF318)19. TRAF3 is a negative regulator of TLR- and TNFR-mediated MAPK activation and has to be degraded for MAPK stimulation19. Instead of activating NF-κB, it activates interferon regulatory factors (IRFs)20. In the third death path, MyD88 DD associates with FADD (Fas-associated death domain) protein, which leads to apoptosis. In the TRIF-dependent pathway, IRFs dimerize and get activated, producing IFNs. Whether Mal and TRAM bind to TLR4 competitively using the same interaction surface has been unknown21, but several studies pointed out that they do182122. This is important since it could explain the outcome of inflammation/cancer-related aberrations or mutations on the Mal and TRAM binding surfaces, or overexpression of either of these. It was suggested that upon engagement of TLR4 with its cognate ligand lipopolysaccharide (LPS), these two pathways are activated sequentially: first the MyD88-dependent and then the TRIF-dependent71218.


The Architecture of the TIR Domain Signalosome in the Toll-like Receptor-4 Signaling Pathway.

Guven-Maiorov E, Keskin O, Gursoy A, VanWaes C, Chen Z, Tsai CJ, Nussinov R - Sci Rep (2015)

Toll-like receptor pathway (adapted from literature121519), in traditional node-and-edge representation, where nodes represent proteins and edges represent interactions between proteins.TLR pathway is complicated and has many branches. Stimulation of TLRs propagate the signal through two parallel paths: MyD88-dependent path (green), which leads to production of pro-inflammatory cytokines, and TRIF-dependent path (orange), which gives rise to transcription of antiviral proteins—interferons—and anti-inflammatory cytokine IL-10. MyD88-mediated pathway also has three branches, namely TRAF6- (green), TRAF3- (orange) (downstream of endosomal TLRs), and FADD-dependent (pink) downstream pathways. For space limitation, we showed TLRs on endosomal membrane as monomers, but they also dimerize upon stimulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544004&req=5

f1: Toll-like receptor pathway (adapted from literature121519), in traditional node-and-edge representation, where nodes represent proteins and edges represent interactions between proteins.TLR pathway is complicated and has many branches. Stimulation of TLRs propagate the signal through two parallel paths: MyD88-dependent path (green), which leads to production of pro-inflammatory cytokines, and TRIF-dependent path (orange), which gives rise to transcription of antiviral proteins—interferons—and anti-inflammatory cytokine IL-10. MyD88-mediated pathway also has three branches, namely TRAF6- (green), TRAF3- (orange) (downstream of endosomal TLRs), and FADD-dependent (pink) downstream pathways. For space limitation, we showed TLRs on endosomal membrane as monomers, but they also dimerize upon stimulation.
Mentions: Toll-like receptors (TLRs) orchestrate the innate and adaptive immune systems1. The TLR pathway (Fig. 1) plays critical roles in almost every phase of tumor development2. Two opposing roles are attributed to TLRs: anti-tumor and pro-tumor actions3. TLR-induced inflammation promotes cancer via proliferative and anti-apoptotic factors4. TLRs form homo- or hetero-dimers and their cytoplasmic Toll/IL-1R homology (TIR) domains associate with TIR domain-containing adaptor molecules to stimulate signaling5. They have six adaptor proteins, Myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like (Mal, also known as TIRAP)6, TIR domain containing adaptor inducing interferon-β (TRIF, also known as TICAM-1)7, TRIF-related adaptor molecule (TRAM, also known as TICAM-2)8, sterile α and heat-armadillo motifs (SARM)9, and B-cell adaptor for PI3K (BCAP)10. TLR signaling induces expression of pro-inflammatory cytokines, interferons (IFNs) and interleukin-10 (IL-10, an anti-inflammatory cytokine). While IFN production suppresses cancer, pro-inflammatory cytokines promote it11. Upon stimulation, TLRs cluster in lipid rafts1213. In their MyD88-dependent pathway, the TLR TIR domains associate with TIR domains of MyD88 and Mal proteins. MyD88 TIR domain is connected through a long linker to its DD. Through its DD, MyD88 can initiate three downstream pathways. In the first, pro-survival inflammatory pathway, it recruits serine/threonine kinases IRAKs (Interleukin-1 receptor-associated kinases) to stimulate the TNF receptor-associated factor 6 (TRAF6), IKK complex and MAPKs, (e.g. ERK, JNK, and p3814) and transcription factors NF-κB, AP-1, and CREB1516, which ultimately result in transcription of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), and IL-1β17. In the second path, MyD88 DD binds to TRAF3 instead of TRAF6 (only TLRs on endosomal membranes recruit TRAF318)19. TRAF3 is a negative regulator of TLR- and TNFR-mediated MAPK activation and has to be degraded for MAPK stimulation19. Instead of activating NF-κB, it activates interferon regulatory factors (IRFs)20. In the third death path, MyD88 DD associates with FADD (Fas-associated death domain) protein, which leads to apoptosis. In the TRIF-dependent pathway, IRFs dimerize and get activated, producing IFNs. Whether Mal and TRAM bind to TLR4 competitively using the same interaction surface has been unknown21, but several studies pointed out that they do182122. This is important since it could explain the outcome of inflammation/cancer-related aberrations or mutations on the Mal and TRAM binding surfaces, or overexpression of either of these. It was suggested that upon engagement of TLR4 with its cognate ligand lipopolysaccharide (LPS), these two pathways are activated sequentially: first the MyD88-dependent and then the TRIF-dependent71218.

Bottom Line: The architecture that we obtain with 8 MyD88 molecules provides the structural basis for the MyD88-templated myddosome helical assembly and receptor clustering; it also provides clues to pro- and anti-inflammatory signaling pathways branching at the signalosome level to Mal/MyD88 and TRAM/TRIF pro- and anti-inflammatory pathways.The assembly of MyD88 death domain (DD) with TRAF3 (anti-viral/anti-inflammatory) and TRAF6 (pro-inflammatory) suggest that TRAF3/TRAF6 binding sites on MyD88 DD partially overlap, as do IRAK4 and FADD.Significantly, the organization illuminates mechanisms of oncogenic mutations, demonstrates that almost all TLR4 parallel pathways are competitive and clarifies decisions at pathway branching points.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey.

ABSTRACT
Activated Toll-like receptors (TLRs) cluster in lipid rafts and induce pro- and anti-tumor responses. The organization of the assembly is critical to the understanding of how these key receptors control major signaling pathways in the cell. Although several models for individual interactions were proposed, the entire TIR-domain signalosome architecture has not been worked out, possibly due to its complexity. We employ a powerful algorithm, crystal structures and experimental data to model the TLR4 and its cluster. The architecture that we obtain with 8 MyD88 molecules provides the structural basis for the MyD88-templated myddosome helical assembly and receptor clustering; it also provides clues to pro- and anti-inflammatory signaling pathways branching at the signalosome level to Mal/MyD88 and TRAM/TRIF pro- and anti-inflammatory pathways. The assembly of MyD88 death domain (DD) with TRAF3 (anti-viral/anti-inflammatory) and TRAF6 (pro-inflammatory) suggest that TRAF3/TRAF6 binding sites on MyD88 DD partially overlap, as do IRAK4 and FADD. Significantly, the organization illuminates mechanisms of oncogenic mutations, demonstrates that almost all TLR4 parallel pathways are competitive and clarifies decisions at pathway branching points. The architectures are compatible with the currently-available experimental data and provide compelling insights into signaling in cancer and inflammation pathways.

No MeSH data available.


Related in: MedlinePlus