LPS-TLR4 Signaling to IRF-3/7 and NF-κB Involves the Toll Adapters TRAM and TRIF

By Katherine A. Fitzgerald, D. C. Rowe, B. Barnes, Daniel R. Caffrey, A. Visintin, E. Latz, Brian G. Monks, P. Pitha, D. Golenbock. Journal of Experimental Medicine, 2003

1,233 citations recorded by the source corpus.

Toll–IL-1–resistance (TIR) domain–containing adaptor-inducing IFN-β (TRIF)–related adaptor molecule (TRAM) is the fourth TIR domain–containing adaptor protein to be described that participates in Toll receptor signaling. Like TRIF, TRAM activates interferon regulatory factor (IRF)-3, IRF-7, and NF-κB-dependent signaling pathways. Toll-like receptor (TLR)3 and 4 activate these pathways to induce IFN-α/β, regulated on activation, normal T cell expressed and secreted (RANTES), and γ interferon–inducible protein 10 (IP-10) expression independently of the adaptor protein myeloid differentiation factor 88 (MyD88). Dominant negative and siRNA studies performed here demonstrate that TRIF functions downstream of both the TLR3 (dsRNA) and TLR4 (LPS) signaling pathways, whereas the function of TRAM is restricted to the TLR4 pathway. TRAM interacts with TRIF, MyD88 adaptor–like protein (Mal)/TIRAP, and TLR4 but not with TLR3. These studies suggest that TRIF and TRAM both function in LPS-TLR4 signaling to regulate the MyD88-independent pathway during the innate immune response to LPS.

Subfields: Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/76eeb40fe116acce49236716af8ffbca3076190f

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Immunology

Citations in the corpus

TLR3: interferon induction by double-stranded RNA including poly(I:C). (2008, background): “The TIR domain of TICAM-1 is essential for binding to the TIR domain of TLR3 and also to the TLR4 adaptor TICAM-2 (also called TRIFrelated adaptor molecule [TRAM]) [53,54].”
Innate Immune Pattern Recognition: A Cell Biological Perspective (2015, neutral): “TLR3 also activates TRIF-dependent signaling, but unlike TLR4, this process does not require TRAM (Figure 4) (159).”
Toll-like receptors in innate immunity. (2004, neutral): “Studies with TRAM-deﬁcient mice and RNAi-mediated knockdown of TRAM expression showed that TRAM is involved in TLR4-mediated, but not TLR3-mediated, activation of IRF-3 and induction of IFN-b - and IFN-inducible genes (88–90).”
Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. (2006, neutral): “MyD88-independent signaling events are controlled by TRIF and TRAM and induce IRF3- dependent type I interferon production (Fitzgerald et al., 2003; Hoebe et al., 2003; Oshiumi et al., 2003a, 2003b; Yamamoto et al., 2003a, 2003b).”