Differential Involvement of BB Loops of Toll-IL-1 Resistance (TIR) Domain-Containing Adapter Proteins in TLR4- versus TLR2-Mediated Signal Transduction

Toshchakov, Vladimir Y.; Basu, Subhendu; Fenton, Matthew J.; Vogel, Stefanie N.

doi:10.4049/jimmunol.175.1.494

Cited by 82 publications

(109 citation statements)

References 48 publications

(63 reference statements)

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“…Furthermore, modeling and functional studies revealed that residues outside of the BB loop play vital roles in TIR domain associations or TLR signaling, such as the CD, DD, and EE loops (11,14,25,(27)(28)(29)(30). These observations make conceptualizing a coherent model of the TIR:TIR domain signaling a challenge, which is further complicated by the findings that the modes of receptor: adapter assembly may differ among different TLR receptors (22,24).…”

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confidence: 95%

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Molecular mechanisms for the subversion of MyD88 signaling by TcpC from virulent uropathogenicEscherichia coli

Snyder

Cirl

Jiang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

108

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The Toll/IL-1 receptor (TIR) domains are crucial signaling modules during innate immune responses involving the Toll-like receptors (TLRs) and IL-1 receptor (IL-1R). Myeloid differential factor 88 (MyD88) is a central TIR domain-containing adapter molecule responsible for nearly all TLR-mediated signaling and is targeted by a TIR domain-containing protein C (TcpC) from virulent uropathogenic Escherichia coli, a common human pathogen. The mechanism of such molecular antagonism has remained elusive. We present the crystal structure of the MyD88 TIR domain with distinct loop conformations that underscore the functional specialization of the adapter, receptor, and microbial TIR domains. Our structural analyses shed light on the genetic mutations at these loops as well as the Poc site. We demonstrate that TcpC directly associates with MyD88 and TLR4 through its predicted DD and BB loops to impair the TLR-induced cytokine induction. Furthermore, NMR titration experiments identify the unique CD, DE, and EE loops from MyD88 at the TcpC-interacting surface, suggesting that TcpC specifically engages these MyD88 structural elements for immune suppression. These findings thus provide a molecular basis for the subversion of TLR signaling by the uropathogenic E. coli virulence factor TcpC and furnish a framework for the design of novel therapeutic agents that modulate immune activation.innate immune cells | bacterial pathogens

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confidence: 95%

“…Genetics and mutagenesis studies have identified the conserved Pro residue and the BB loop (box 2) as essential for TLR signaling (10,(20)(21)(22)(23). However, the importance of the Pro residue or the BB loop was called into question by others (6,13,(24)(25)(26).…”

mentioning

confidence: 99%

Molecular mechanisms for the subversion of MyD88 signaling by TcpC from virulent uropathogenicEscherichia coli

Snyder

Cirl

Jiang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

108

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“…The MyD88 and TRIF inhibitory peptides that correspond to the sequence of the BB-loop of MyD88 (RDVLPGT) and TRIF (FCEEFQVPGRGELH), respectively, serve as decoys by binding to the TIR domains and interfering with TLR-adaptor interactions (17,18). The control peptides consist of the protein transduction sequence alone, which renders the peptides cell-permeable.…”

Section: Inhibition Of Trif Myd88 Hmgb1 Hsp70 and Its Receptorsmentioning

confidence: 99%

Cross-Presentation of the Oncofetal Tumor Antigen 5T4 from Irradiated Prostate Cancer Cells—A Key Role for Heat-Shock Protein 70 and Receptor CD91

Salimu

Spary

Al-Taei

et al. 2015

Cancer Immunology Research

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Immune responses contribute to the success of radiotherapy of solid tumors; however, the mechanism of triggering CD8 þ T-cell responses is poorly understood. Antigen cross-presentation from tumor cells by dendritic cells (DC) is a likely dominant mechanism to achieve CD8 þ T-cell stimulation. We established a cross-presentation model in which DCs present a naturally expressed oncofetal tumor antigen (5T4) from irradiated DU145 prostate cancer cells to 5T4-specific T cells. The aim was to establish which immunogenic signals are important in radiation-induced cross-presentation. Radiation (12 Gy) caused G 2 -M cell-cycle arrest and cell death, increased cellular 5T4 levels, high-mobility protein group-B1 (HMGB1) release, and surface calreticulin and heat-shock protein-70 (Hsp70) expression in DU145 cells. DCs phagocytosed irradiated tumor cells efficiently, followed by upregulation of CD86 on phagocytic DCs. CD8 þ 5T4-specific T cells, stimulated with these DCs, proliferated and produced IFNg. Inhibition of HMGB1 or the TRIF/MyD88 pathway only had a partial effect on T-cell stimulation. Unlike previous investigators, we found no evidence that DCs carrying Asp299Gly Toll-like receptor-4 (TLR4) single-nucleotide polymorphism had impaired ability to cross-present tumor antigen. However, pretreatment of tumor cells with Hsp70 inhibitors resulted in a highly statistically significant and robust prevention of antigen cross-presentation and CD86 upregulation on DCs cocultured with irradiated tumor cells. Blocking the Hsp70 receptor CD91 also abolished cross-presentation. Together, the results from our study demonstrate that irradiation induces immunologically relevant changes in tumor cells, which can trigger CD8 þ T-cell responses via a predominantly Hsp70-dependent antigen cross-presentation process. Cancer Immunol Res; 3(6); 678-88. Ó2015 AACR.

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“…For antagonist inhibition assay, zebrafish were pretreated 1 h via i.p. with two TRIF antagonist peptides (with a penetration sequence at the N terminus) derived from a mice model (41,42). The sequences of the peptides for DrTRIF (DrT1 and DrT2) and control are shown as follows: RQIKIWFQNRRMKWKK-CIEDAI DNSAFV-NH2 (DrT1), RQIKIWFQNRRMKWKK-FSEDFAQAGRSTLR-NH2 (DrT2), and RQIKIWFQNRRMKWKK-SLHGRGDPMEAFII-NH2 (DrControl).…”

Section: Evaluation Of Drsigirr and Drtrif In Liver Inflammationmentioning

confidence: 99%

Characterization of SIGIRR/IL-1R8 Homolog from Zebrafish Provides New Insights into Its Inhibitory Role in Hepatic Inflammation

Feng

Nie

et al. 2016

The Journal of Immunology

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Single Ig IL-1R–related molecule (SIGIRR, also called IL-1R8 or Toll/IL-1R [TIR]8), a negative regulator for Toll/IL-1R signaling, plays critical roles in innate immunity and various diseases in mammals. However, the occurrence of this molecule in ancient vertebrates and its function in liver homeostasis and disorders remain poorly understood. In this study, we identified a SIGIRR homology from zebrafish (Danio rerio [DrSIGIRR]) by using a number of conserved structural and functional hallmarks to its mammalian counterparts. DrSIGIRR was highly expressed in the liver. Ablation of DrSIGIRR by lentivirus-delivered small interfering RNA in the liver significantly enhanced hepatic inflammation in response to polyinosinic-polycytidylic acid [poly(I:C)] stimulation, as shown by the upregulation of inflammatory cytokines and increased histological disorders. In contrast, depletion of TIR domain–containing adaptor inducing IFN-β (TRIF) or administration of TRIF signaling inhibitor extremely abrogated the poly(I:C)-induced hepatic inflammation. Aided by the zebrafish embryo model, overexpression of DrSIGIRR in vivo significantly inhibited the poly(I:C)- and TRIF-induced NF-κB activations; however, knockdown of DrSIGIRR promoted such activations. Furthermore, pull-down and Duolink in situ proximity ligation assay assays showed that DrSIGIRR can interact with the TRIF protein. Results suggest that DrSIGIRR plays an inhibitory role in TRIF-mediated inflammatory reactions by competitive recruitment of the TRIF adaptor protein from its TLR3/TLR22 receptor. To our knowledge, this study is the first to report a functional SIGIRR homolog that existed in a lower vertebrate. This molecule is essential to establish liver homeostasis under inflammatory stimuli. Overall, the results will enrich the current knowledge about SIGIRR-mediated immunity and disorders in the liver.

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Differential Involvement of BB Loops of Toll-IL-1 Resistance (TIR) Domain-Containing Adapter Proteins in TLR4- versus TLR2-Mediated Signal Transduction

Cited by 82 publications

References 48 publications

Molecular mechanisms for the subversion of MyD88 signaling by TcpC from virulent uropathogenicEscherichia coli

Molecular mechanisms for the subversion of MyD88 signaling by TcpC from virulent uropathogenicEscherichia coli

Cross-Presentation of the Oncofetal Tumor Antigen 5T4 from Irradiated Prostate Cancer Cells—A Key Role for Heat-Shock Protein 70 and Receptor CD91

Characterization of SIGIRR/IL-1R8 Homolog from Zebrafish Provides New Insights into Its Inhibitory Role in Hepatic Inflammation

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