Noncanonical Autophagy Is Required for Type I Interferon Secretion in Response to DNA-Immune Complexes Academic Article uri icon

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abstract

  • Toll-like receptor-9 (TLR9) is largely responsible for discriminating self from pathogenic DNA. However, association of host DNA with autoantibodies activates TLR9, inducing the pathogenic secretion of type I interferons (IFNs) from plasmacytoid dendritic cells (pDCs). Here, we found that in response to DNA-containing immune complexes (DNA-IC), but not to soluble ligands, IFN-α production depended upon the convergence of the phagocytic and autophagic pathways, a process called microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis (LAP). LAP was required for TLR9 trafficking into a specialized interferon signaling compartment by a mechanism that involved autophagy-related proteins, but not the conventional autophagic preinitiation complex, or adaptor protein-3 (AP-3). Our findings unveil a new role for nonconventional autophagy in inflammation and provide one mechanism by which anti-DNA autoantibodies, such as those found in several autoimmune disorders, bypass the controls that normally restrict the apportionment of pathogenic DNA and TLR9 to the interferon signaling compartment.

authors

  • Henault, Jill
  • Martinez, Jennifer
  • Riggs, Jeffrey M
  • Tian, Jane
  • Mehta, Payal
  • Clarke, Lorraine
  • Sasai, Miwa
  • Latz, Eicke
  • Brinkmann, Melanie M
  • Iwasaki, Akiko
  • Coyle, Anthony J
  • Kolbeck, Roland
  • Green, Douglas R
  • Sanjuan, Miguel A

publication date

  • December 2012