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

Miwa Sasai, Melissa M. Linehan, Akiko Iwasaki. Science 329, 1530 (2010)

Speaker: Yin-Chiou, Luo (羅尹秋)                               Time:14:00~15:00, Dec.22, 2010

Commentator: Pei-Jane Tsai, Ph.D. (蔡佩珍老師)       Place: Room 601

Abstract

        The Toll-like receptor (TLR) family is a group of innate immune receptors recognizing microbial components during infection. Endosomal TLR 7 and 9 mainly expressed in plasmacytoid dendritic cells (pDCs) detect microbial nucleic acids to induce proinflammatory cytokines and type I interferon. Adaptor protein 3(AP3) is endolysosomal adaptor which mediates trafficking of cargo proteins to lysosome-related organelles (LROs). Given the fact that TLR9 signaling is associated with endolysosomal trafficking, the authors aim to determine whether AP3 is involved in TLR9 trafficking and signaling. They first found that upon stimulation with the TLR9 ligand CpG-A, AP3-deficient pDCs failed to produce IFNα but still produced the normal level of IL-12. Furthermore, in AP3-deficient macrophages stimulated with DOTAP-CpG-A, TLR9 located at early endosomesbut failed to migrate into late endolysosomes. The authors therefore hypothesized that TLR9 signals from two distinct endolysosomal compartments: NF-κB endosomes and IRF7 endosomes. Furthermore, the confocal microscopy and co-IP data showed that AP3 was associated with TRAF3 and IRF7, both of which are essential for type-I IFN production. A recombinant TRAF3 with a phospholipids-binding PH domain was generated for the rescued experiment. Expression of PH-TRAF3 in the AP3-deficient macrophage led to IFNα production through targeting to the TLR9-containing NF-κB endosomes. Collectively, these data suggest that TLR9 triggers downstream signaling at two endolysosomal compartments. AP-3 is an essential adaptor for escorting TLR9 to the IRF7 endosomes for type-I IFN production.

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