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

✍ Scribed by Sasai, Miwa (author);Linehan, Melissa M. (author);Iwasaki, Akiko (author)

• Book ID: 127302778
• Publisher: American Association for the Advancement of Science
• Year: 2010
• Tongue: English
• Weight: 956 KB
• Volume: 329
• Category: Article
• ISSN: 0036-8075
• DOI: 10.1126/science.1187029

✦ Synopsis

Location Matters

Plasmacytoid dendritic cells (pDCs), an immune cell 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.
(p.
1530
) now show that subcellular localization is key. Cells from mice deficient in the Adapter 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.