TRAM is required for TLR2 endosomal signaling to type I IFN induction.
Item Type:Journal Article
Citation:Stack J, Doyle SL, Connolly DJ, Reinert LS, O'Keeffe KM, McLoughlin RM, Paludan SR, Bowie AG, TRAM is required for TLR2 endosomal signaling to type I IFN induction., Journal of immunology (Baltimore, Md. : 1950), 193, 12, 2014, 6090-102
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Detection of microbes by TLRs on the plasma membrane leads to the induction of pro-inflammatory 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, while endosomal TLR4 signaling to IRF3 via TRIF requires the TIR sorting adaptor TRAM. Similar to TLR4 homodimers, TLR2 heterodimers can also induce both pro-inflammatory cytokines and type I IFNs. TLR2 plasma membrane signaling to NF-κB is known to require MyD88 and Mal, while endosomal IRF activation by TLR2 requires MyD88. However whether, like TLR4, TLR2 requires a sorting adaptor for endosomal signaling was unclear. Here 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.
Type of material:Journal Article
Series/Report no:Journal of immunology (Baltimore, Md. : 1950)
Availability:Full text available