SCIENCE SIGNALING

An Inside Job?

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Science  04 Apr 2008:
Vol. 320, Issue 5872, pp. 23
DOI: 10.1126/science.320.5872.23c

Toll-like receptor (TLR) 4, which recognizes bacterial cell wall components, interacts with the TIRAP-MyD88 pair of adaptor proteins to stimulate the production of inflammatory cytokines, and also with the TRAM-TRIF adaptor pair to stimulate the production of type I interferons. Curious about how TLR4 coordinates activation of these two signaling pathways, Kagan et al. analyzed TLR4 location in macrophages and found that it was present both at the plasma membrane and in early endosomes. Inhibition of dynamin-dependent endocytosis prevented lipopolysaccharide (LPS)-induced internalization of endogenous TLR4 and blocked TRAM-TRIF-dependent phosphorylation of the transcription factor IRF3 (and the expression of target genes) whereas TIRAP-MyD88-dependent phosphorylation of p38 mitogen-activated protein kinase and IκBα degradation were unaffected. Although TIRAP localized to the plasma membrane, TRAM was present at both the plasma membrane and in early endosomes. Analyses of LPS-induced cytokine production by TRAM localization mutants indicated that TLR4 signaling through TRAMTRIF took place in endosomes. Noting that no known TLRs stimulate type I interferon production from the plasma membrane (TLR4 had been thought to be the lone exception), the authors propose that TLR4 stimulates TIRAP-MyD88 signaling from the cell surface and initiates TRAM-TRIF signaling only after internalization. — EMA

Nat. Immunol. 9, 361 (2008).

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