The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy.
The mitochondrial protein MAVS (also known as IPS-1, VISA, and CARDIF) interacts with RIG-I-like receptors (RLRs) to induce type I interferon (IFN-I). NLRX1 is a mitochondrial nucleotide-binding, leucine-rich repeats (NLR)-containing protein that attenuates MAVS-RLR signaling. Using Nlrx1(-/-) cells, we confirmed that NLRX1 attenuated IFN-I production, but additionally promoted autophagy during ... viral infection. This dual function of NLRX1 paralleled the previously described functions of the autophagy-related proteins Atg5-Atg12, but NLRX1 did not associate with Atg5-Atg12. High-throughput quantitative mass spectrometry and endogenous protein-protein interaction revealed an NLRX1-interacting partner, mitochondrial Tu translation elongation factor (TUFM). TUFM interacted with Atg5-Atg12 and Atg16L1 and has similar functions as NLRX1 by inhibiting RLR-induced IFN-I but promoting autophagy. In the absence of NLRX1, increased IFN-I and decreased autophagy provide an advantage for host defense against vesicular stomatitis virus. This study establishes a link between an NLR protein and the viral-induced autophagic machinery via an intermediary partner, TUFM.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Autophagy, Carrier Proteins, Cytokines, DEAD-box RNA Helicases, Fibroblasts, Gene Expression Regulation, HEK293 Cells, Humans, Interferon Type I, Macrophages, Peritoneal, Mice, Microtubule-Associated Proteins, Mitochondrial Proteins, Molecular Sequence Data, Multiprotein Complexes, Peptide Elongation Factor Tu, Protein Interaction Mapping, Proteins, Recombinant Fusion Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Specific Pathogen-Free Organisms, Vesiculovirus
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Autophagy, Carrier Proteins, Cytokines, DEAD-box RNA Helicases, Fibroblasts, Gene Expression Regulation, HEK293 Cells, Humans, Interferon Type I, Macrophages, Peritoneal, Mice, Microtubule-Associated Proteins, Mitochondrial Proteins, Molecular Sequence Data, Multiprotein Complexes, Peptide Elongation Factor Tu, Protein Interaction Mapping, Proteins, Recombinant Fusion Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Specific Pathogen-Free Organisms, Vesiculovirus
Immunity
Date: Jun. 29, 2012
PubMed ID: 22749352
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