Location Matters

Science Signaling  21 Sep 2010:
Vol. 3, Issue 140, pp. ec292
DOI: 10.1126/scisignal.3140ec292

Plasmacytoid dendritic cells (pDCs), immune cells specialized to respond to viral infections, use Toll-like receptors (TLRs) 7 and 9 expressed in endosomes to sense viral nucleic acids. Triggering of TLR7 or -9 results in the induction of two distinct signaling pathways, one that leads to the production of proinflammatory cytokines and another that induces the expression of antiviral type I interferons. How one receptor can trigger two distinct signaling pathways, however, is not clear. Sasai et al. now show that subcellular localization is key. Cells from mice deficient in the adaptor protein 3 (AP-3) complex, which regulates protein sorting to intracellular vesicles, did not produce type I interferons in response to TLR9 ligand, but proinflammatory cytokine production remained intact. AP-3 was required for trafficking of TLR9 from early endosomes, where proinflammatory signaling can occur, to lysosome-related organelles, where the signaling machinery required for type I interferon induction is located. Such spatial segregation may represent a common mechanism whereby activation of one receptor can result in the induction of multiple independent signaling cascades.

M. Sasai, M. M. Linehan, A. Iwasaki, Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3. Science 329, 1530–1534 (2010). [Abstract] [Full Text]