ArticleThe Journal of biological chemistry2012
Poxviral protein A46 antagonizes Toll-like receptor 4 signaling by targeting BB loop motifs in Toll-IL-1 receptor adaptor proteins to disrupt receptor:adaptor interactions.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 40 citations in OpenAlex.
- TIR domain proteins: regulatory mechanisms in the tumor immune microenvironment, clinical translation strategies, and prospects for precision therapy applications.Frontiers in immunology · 2025Pooled it
- Therapeutic Poxviruses Induce the Secretion of Immunostimulating and Anti-Tumoral Extracellular Vesicles.Journal of extracellular vesicles · 2026Article
- Transcriptomic Assessment of Host Responses in Vaccinia and Venezuelan Equine Encephalitis Virus-Infected Human Dendritic Cells.Biomolecules · 2026Article
- The monkeypox virus-host interplays.Cell insight · 2024Review
- Integrated approaches for the recognition of small molecule inhibitors for Toll-like receptor 4.Computational and structural biotechnology journal · 2023Article
- Battle Royale: Innate Recognition of Poxviruses and Viral Immune Evasion.Biomedicines · 2021Review
- Review
- Leaky scanning translation generates a second A49 protein that contributes to vaccinia virus virulence.The Journal of general virology · 2020Article
- Paradoxical Roles of the MAL/Tirap Adaptor in Pathologies.Frontiers in immunology · 2020Review
- NF-κB activation is a turn on for vaccinia virus phosphoprotein A49 to turn off NF-κB activation.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Review
- Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Encapsulated Hsp70 decreases endotoxin-induced production of ROS and TNFα in human phagocytes.Cell stress & chaperones · 2017Article
- Vaccinia Virus Immunomodulator A46: A Lipid and Protein-Binding Scaffold for Sequestering Host TIR-Domain Proteins.PLoS pathogens · 2016Article
- Multiple Bcl-2 family immunomodulators from vaccinia virus regulate MAPK/AP-1 activation.The Journal of general virology · 2016Article
- Exogenous heat shock protein HSP70 reduces response of human neuroblastoma cells to lipopolysaccharide.Doklady. Biochemistry and biophysics · 2016Article
- Article
- Wogonin inhibits LPS-induced inflammatory responses in rat dorsal root ganglion neurons via inhibiting TLR4-MyD88-TAK1-mediated NF-κB and MAPK signaling pathway.Cellular and molecular neurobiology · 2015Article
- Borna disease virus possesses an NF-ĸB inhibitory sequence in the nucleoprotein gene.Scientific reports · 2015Article
- Toll-like receptor 4 inhibition within the paraventricular nucleus attenuates blood pressure and inflammatory response in a genetic model of hypertension.Journal of neuroinflammation · 2015Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Toll-like receptors (TLRs) have an anti-viral role in that they detect viruses, leading to cytokine and IFN induction, and as such are targeted by viruses for immune evasion. TLR4, although best known for its role in recognizing bacterial LPS, is also strongly implicated in the immune response to viruses. We previously showed that the poxviral protein A46 inhibits TLR4 signaling and interacts with Toll-IL-1 receptor (TIR) domain-containing proteins of the receptor complex. However the exact molecular mechanism whereby A46 disrupts TLR4 signaling remains to be established, and may yield insight into how the TLR4 complex functions, since viruses often optimally target key residues and motifs on host proteins for maximal efficiency. Here we show that A46 targets the BB loop motif of TIR proteins and thereby disrupts receptor:adaptor (TLR4:Mal and TLR4:TRAM), but not receptor:receptor (TLR4:TLR4) nor adaptor:adaptor (Mal:MyD88, TRAM:TRIF, and Mal:Mal) TIR interactions. The requirement for an intact BB loop for TIR adaptor interactions correlated with the protein:protein interfaces antagonized by A46. We previously discovered a peptide fragment derived from A46 termed VIPER (Viral Inhibitory Peptide of TLR4), which specifically inhibits TLR4 responses. Here we demonstrate that the region of A46 from which VIPER is derived represents the TLR4-specific inhibitory motif of the intact protein, and is essential for A46:TRAM interactions. This study provides the molecular basis for pathogen subversion of TLR4 signaling and clarifies the importance of TIR motif BB loops, which have been selected for viral antagonism, in the formation of the TLR4 complex.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.