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Identification of a new autoinhibitory domain of interferon-beta promoter stimulator-1 (IPS-1) for the tight regulation of oligomerization-driven signal activation.

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.
AuthorsKiyohiro Takahasi, Koji Onomoto, Masataka Horiuchi, Hiroki Kato, Takashi Fujita, Mitsutoshi Yoneyama
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 517 Issue 4 Pg. 662-669 (10 01 2019) ISSN: 1090-2104 [Electronic] United States
PMID31395337 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2019 Elsevier Inc. All rights reserved.
Chemical References
  • Adaptor Proteins, Signal Transducing
  • IPS-1 protein, mouse
  • Interferon Type I
  • Mutant Proteins
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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