ArticleJournal of immunology (Baltimore, Md. : 1950)2014
TRAM is required for TLR2 endosomal signaling to type I IFN induction.
Article in Journal of immunology (Baltimore, Md. : 1950), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 107 citations in OpenAlex.
- Article
- TGFβ primes alveolar-like macrophages to induce type I IFN following TLR2 activation.Journal of immunology (Baltimore, Md. : 1950) · 2026Article
- RANKL inhibits macrophage proinflammatory Toll-like receptor 2 and 4 signaling and impairs killing of intracellular bacteria.ImmunoHorizons · 2026Article
- Endosome restricted human TLR1 polymorphism highlights a role for MyD88 in Pam3CSK4 detection.PloS one · 2026Article
- Review
- Lactobacilli-Derived Microbe-Associated Molecular Patterns (MAMPs) in Host Immune Modulation.Biomolecules · 2025Review
- A citrullinated histone H3 monoclonal antibody for immune modulation in sepsis.Nature communications · 2025Article
- Type I interferons regulate nitric oxide production inFrontiers in immunology · 2025Article
- Article
- Mannose and Lactobionic Acid in Nasal Vaccination: Enhancing Antigen Delivery via C-Type Lectin Receptors.Pharmaceutics · 2024Review
- Streptococcus suis Serotype 2 Type IV Secretion Effector SspA-1 Induces Proinflammatory Cytokine Production via TLR2 Endosomal and Type I Interferon Signaling.The Journal of infectious diseases · 2024Article
- An immune-adrenergic pathway induces lethal levels of platelet-activating factor in mice.Communications biology · 2024Article
- Aerobic glycolysis of bronchial epithelial cells rewiresInfection and immunity · 2024Article
- Toll-like receptor 4 pathway evolutionary trajectory and functional emergence.Frontiers in immunology · 2024Article
- Article
- Review
- Type-I interferons promote innate immune tolerance in macrophages exposed to Mycobacterium ulcerans vesicles.PLoS pathogens · 2023Article
- Simultaneous control of infection and inflammation with keratin-derived antibacterial peptides targeting TLRs and co-receptors.Science translational medicine · 2023Article
- YULINK regulates vascular formation in zebrafish and HUVECs.Biological research · 2023Article
- The macrophage infectivity potentiator ofFrontiers in immunology · 2023Article
17 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
Detection of microbes by TLRs on the plasma membrane leads to the induction of proinflammatory cytokines such as TNF-α, via activation of NF-κB. Alternatively, activation of endosomal TLRs leads to the induction of type I IFNs via IFN regulatory factors (IRFs). TLR4 signaling from the plasma membrane to NF-κB via the Toll/IL-1R (TIR) adaptor protein MyD88 requires the TIR sorting adaptor Mal, whereas endosomal TLR4 signaling to IRF3 via the TIR domain-containing adaptor-inducing IFN-β (TRIF) requires the TRIF-related adaptor molecule (TRAM). Similar to TLR4 homodimers, TLR2 heterodimers can also induce both proinflammatory cytokines and type I IFNs. TLR2 plasma membrane signaling to NF-κB is known to require MyD88 and Mal, whereas endosomal IRF activation by TLR2 requires MyD88. However, it was unclear whether TLR2 requires a sorting adaptor for endosomal signaling, like TLR4 does. In this study, we show that TLR2-dependent IRF7 activation at the endosome is both Mal- and TRAM-dependent, and that TRAM is required for the TLR2-dependent movement of MyD88 to endosomes following ligand engagement. TRAM interacted with both TLR2 and MyD88, suggesting that TRAM can act as a bridging adapter between these two molecules. Furthermore, infection of macrophages lacking TRAM with herpes viruses or the bacterium Staphylococcus aureus led to impaired induction of type I IFN, indicating a role for TRAM in TLR2-dependent responses to human pathogens. Our work reveals that TRAM acts as a sorting adaptor not only for TLR4, but also for TLR2, to facilitate signaling to IRF7 at the endosome, which explains how TLR2 is capable of causing type I IFN induction.
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Registered trials
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.