Noncanonical Autophagy Is Required for Type I Interferon Secretion in Response to DNA-Immune Complexes.
Henault, Jill 1,7; Martinez, Jennifer 3,7; Riggs, Jeffrey M. 1; Tian, Jane 1; Mehta, Payal 1; Clarke, Lorraine 2; Sasai, Miwa 6; Latz, Eicke 4; Brinkmann, Melanie M. 5; Iwasaki, Akiko 6; Coyle, Anthony J. 1,8; Kolbeck, Roland 1; Green, Douglas R. 3,9,∗; Sanjuan, Miguel A. 1,9,∗∗
[Article]
Immunity.
37(6):986-997, December 2012.
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: 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-[alpha] 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 Fc[gamma]R signaling -> LAP, which is distinct from conventional autophagy, is required for IFN-[alpha] secretion -> LAP is not required for TLR9-mediated TNF secretion -> LAP allows trafficking of TLR9 into a specialized IFN-signaling compartment
(C) 2012Elsevier, Inc.