Immunity
Volume 37, Issue 6, 14 December 2012, Pages 986-997
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Article
Noncanonical Autophagy Is Required for Type I Interferon Secretion in Response to DNA-Immune Complexes

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Summary

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.

Highlights

► DNA-ICs recruit TLR9 and autophagy protein LC3 to phagosomes through FcγR signaling ► LAP, which is distinct from conventional autophagy, is required for IFN-α secretion ► LAP is not required for TLR9-mediated TNF secretion ► LAP allows trafficking of TLR9 into a specialized IFN-signaling compartment

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These authors contributed equally to this work

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Present address: Pfizer, 200 Cambridgepark Drive, Cambridge, MA 02140-2368

9

These authors contributed equally to this work