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Science 329 (5998): 1530-1534

Copyright © 2010 by the American Association for the Advancement of Science

Bifurcation of Toll-Like Receptor 9 Signaling by Adaptor Protein 3

Miwa Sasai, Melissa M. Linehan, Akiko Iwasaki*

Abstract: Endosomal Toll-like receptors (TLRs) 7 and 9 recognize viral pathogens and induce signals leading to the activation of nuclear factor {kappa}B (NF-{kappa}B)–dependent proinflammatory cytokines and interferon regulatory factor 7 (IRF7)–dependent type I interferons (IFNs). Recognition of viral nucleic acids by TLR9 requires its cleavage in the endolysosomal compartment. Here, we show that TLR9 signals leading to the activation of type I IFN, but not proinflammatory cytokine genes, require TLR9 trafficking from endosomes to a specialized lysosome-related organelle. Furthermore, we identify adapter protein-3 as the protein complex responsible for the trafficking of TLR9 to this subcellular compartment. Our results reveal an intracellular mechanism for bifurcation of TLR9 signals by selective receptor trafficking within the endosomal system.

Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.

* To whom correspondence should be addressed. E-mail: akiko.iwasaki{at}yale.edu

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