Negative regulation of RIG-I-mediated innate antiviral signaling by SEC14L1

J Virol. 2013 Sep;87(18):10037-46. doi: 10.1128/JVI.01073-13. Epub 2013 Jul 10.

Abstract

Retinoic acid-inducible gene I (RIG-I) is a key sensor for recognizing nucleic acids derived from RNA viruses and triggers beta interferon (IFN-β) production. Because of its important role in antiviral innate immunity, the activity of RIG-I must be tightly controlled. Here, we used yeast two-hybrid screening to identify a SEC14 family member, SEC14L1, as a RIG-I-associated negative regulator. Transfected SEC14L1 interacted with RIG-I, and endogenous SEC14L1 associated with RIG-I in a viral infection-inducible manner. Overexpression of SEC14L1 inhibited transcriptional activity of the IFN-β promoter induced by RIG-I but not TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3). Knockdown of endogenous SEC14L1 in both HEK293T cells and HT1080 cells potentiated RIG-I and Sendai virus-triggered IFN-β production as well as attenuated the replication of Newcastle disease virus. SEC14L1 interacted with the N-terminal domain of RIG-I (RIG-I caspase activation and recruitment domain [RIG-I-CARD]) and competed with VISA/MAVS/IPS-1/Cardif for RIG-I-CARD binding. Domain mapping further indicated that the PRELI-MSF1 and CRAL-TRIO domains but not the GOLD domain of SEC14L1 are required for interaction and inhibitory function. These findings suggest that SEC14L1 functions as a novel negative regulator of RIG-I-mediated antiviral signaling by preventing RIG-I interaction with the downstream effector.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / immunology*
  • DEAD-box RNA Helicases / metabolism
  • Down-Regulation
  • Gene Expression
  • Gene Knockdown Techniques
  • Humans
  • Newcastle disease virus / immunology*
  • Protein Binding
  • Protein Interaction Mapping
  • RNA, Viral / immunology*
  • RNA, Viral / metabolism
  • Receptors, Immunologic
  • Sendai virus / immunology*
  • Signal Transduction*
  • Two-Hybrid System Techniques

Substances

  • Carrier Proteins
  • RNA, Viral
  • Receptors, Immunologic
  • SEC14L1 protein, human
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases