Abstract |
Upon viral infection, retinoic acid-inducible gene-I (RIG-I)-like receptors detect viral foreign RNAs and transmit anti-viral signals via direct interaction with the downstream mitochondrial adaptor molecule, interferon (IFN)-β promoter stimulator-1 (IPS-1), to inhibit viral replication. Although IPS-1 is known to form prion-like oligomers on mitochondria to activate signaling, the mechanisms that regulate oligomer formation remain unclear. Here, we identified an autoinhibitory domain (AD) at amino acids 180-349 to suppress oligomerization of IPS-1 in a resting state and regulate activation of downstream signaling. Size exclusion chromatography (SEC) analysis demonstrated that AD was required to suppress auto-oligomerization of the caspase recruitment domain (CARD) of IPS-1 via intramolecular interactions. This was supported by the observation that cleavage of a peptide bond between IPS-1 CARD and AD by Tobacco Etch virus ( TEV) protease relieved autoinhibition. Conversely, deletion of this domain from IPS-1 enhanced signal activation in IFN-reporter assays, suggesting that IPS-1 AD played a critical role in the regulation of IPS-1-mediated anti-viral signal activation. These findings revealed novel molecular interactions involved in the tight regulation of innate anti-viral immunity.
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Authors | Kiyohiro Takahasi, Koji Onomoto, Masataka Horiuchi, Hiroki Kato, Takashi Fujita, Mitsutoshi Yoneyama |
Journal | Biochemical and biophysical research communications
(Biochem Biophys Res Commun)
Vol. 517
Issue 4
Pg. 662-669
(10 01 2019)
ISSN: 1090-2104 [Electronic] United States |
PMID | 31395337
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2019 Elsevier Inc. All rights reserved. |
Chemical References |
- Adaptor Proteins, Signal Transducing
- IPS-1 protein, mouse
- Interferon Type I
- Mutant Proteins
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Topics |
- Adaptor Proteins, Signal Transducing
(chemistry, metabolism)
- Amino Acid Sequence
- Animals
- Interferon Type I
(metabolism)
- Mice
- Mutant Proteins
(chemistry, metabolism)
- Protein Binding
- Protein Domains
- Protein Multimerization
- Sequence Deletion
- Signal Transduction
- Structure-Activity Relationship
- Up-Regulation
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