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Noncanonical autophagy is required for type I interferon secretion in response to DNA-immune complexes.
Henault, Jill Martinez, Jennifer Riggs, Jeffrey M Tian, Jane Mehta, Payal Clarke, Lorraine Sasai, Miwa Latz, Eicke Brinkmann, Melanie M Iwasaki, Akiko
Henault, Jill
Martinez, Jennifer
Riggs, Jeffrey M
Tian, Jane
Mehta, Payal
Clarke, Lorraine
Sasai, Miwa
Latz, Eicke
Brinkmann, Melanie M
Iwasaki, Akiko
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2012-12-14
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original manuscript
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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.
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Noncanonical autophagy is required for type I interferon secretion in response to DNA-immune complexes. 2012, 37 (6):986-97 Immunity
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en
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1097-4180
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