| First Author | Hayashi K | Year | 2018 |
| Journal | Sci Signal | Volume | 11 |
| Issue | 528 | PubMed ID | 29717061 |
| Mgi Jnum | J:282112 | Mgi Id | MGI:6380797 |
| Doi | 10.1126/scisignal.aan4144 | Citation | Hayashi K, et al. (2018) The interaction between IKKalpha and LC3 promotes type I interferon production through the TLR9-containing LAPosome. Sci Signal 11(528) |
| abstractText | Toll-like receptor 9 (TLR9) recognizes DNA in endosomes and activates distinct signaling pathways to stimulate the production of proinflammatory cytokines and type I interferons (IFNs). The assembly of signaling platforms on microtubule-associated proteins 1A/1B-light chain 3 (LC3)-decorated endosomal vesicles is required to transduce TLR9 signals that stimulate the production of IFN but not interleukin-12 p40 (IL-12p40). LC3-associated phagocytosis (LAP), a form of noncanonical autophagy, is critical for the activation of interferon regulatory factor 7 (IRF7) and for IFN synthesis. We showed that after the stimulation of TLR9 by CpG oligonucleotides, the autophagy protein LC3 and the kinase IKKalpha were recruited to endosomes that contained TLR9. The recruitment of IKKalpha and LC3 to such signaling endosomes was not stimulated by catalysts of classical autophagosome formation but involved LAP formation, which required ATG5 but not FIP200. In addition, we found that the LC3-IKKalpha complex further associated with both TRAF3 and IRF7. We identified three putative LC3-interacting regions (LIRs) in IKKalpha, and mutagenesis suggested that two of these were critical for direct binding to LC3. Moreover, mutation of the same LIR sequences failed to rescue type I IFN production in IKKalpha-deficient dendritic cells upon reconstitution. Together, these data suggest a direct link between LAP formation and IKKalpha recruitment downstream of TLR9 activation that is necessary to facilitate type I IFN production. |
