http://hdl.handle.net/10033/128112 Mon, 20 May 2013 05:06:56 GMT 2013-05-20T05:06:56Z http://hdl.handle.net/10033/281033 Title: Noncanonical autophagy is required for type I interferon secretion in response to DNA-immune complexes. 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 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. Fri, 14 Dec 2012 00:00:00 GMT http://hdl.handle.net/10033/281033 2012-12-14T00:00:00Z http://hdl.handle.net/10033/246951 Title: Viral mediated redirection of NEMO/IKKγ to autophagosomes curtails the inflammatory cascade. Authors: Fliss, Patricia M; Jowers, Tali Pechenick; Brinkmann, Melanie M; Holstermann, Barbara; Mack, Claudia; Dickinson, Paul; Hohenberg, Heinrich; Ghazal, Peter; Brune, Wolfram Abstract: The early host response to viral infections involves transient activation of pattern recognition receptors leading to an induction of inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα). Subsequent activation of cytokine receptors in an autocrine and paracrine manner results in an inflammatory cascade. The precise mechanisms by which viruses avert an inflammatory cascade are incompletely understood. Nuclear factor (NF)-κB is a central regulator of the inflammatory signaling cascade that is controlled by inhibitor of NF-κB (IκB) proteins and the IκB kinase (IKK) complex. In this study we show that murine cytomegalovirus inhibits the inflammatory cascade by blocking Toll-like receptor (TLR) and IL-1 receptor-dependent NF-κB activation. Inhibition occurs through an interaction of the viral M45 protein with the NF-κB essential modulator (NEMO), the regulatory subunit of the IKK complex. M45 induces proteasome-independent degradation of NEMO by targeting NEMO to autophagosomes for subsequent degradation in lysosomes. We propose that the selective and irreversible degradation of a central regulatory protein by autophagy represents a new viral strategy to dampen the inflammatory response. Wed, 01 Feb 2012 00:00:00 GMT http://hdl.handle.net/10033/246951 2012-02-01T00:00:00Z