ARF-like protein 16 (ARL16) inhibits RIG-I by binding with its C-terminal domain in a GTP-dependent manner

J Biol Chem. 2011 Mar 25;286(12):10568-80. doi: 10.1074/jbc.M110.206896. Epub 2011 Jan 13.

Abstract

Retinoic acid-inducible gene I (RIG-I) recognizes RNA virus-derived nucleic acids, which leads to the production of type I interferon (IFN) in most cell types. Tight regulation of RIG-I activity is important to prevent ultra-immune responses. In this study, we identified an ARF-like (ARL) family member, ARL16, as a protein that interacts with RIG-I. Overexpression of ARL16, but not its homologous proteins ARL1 and ARF1, inhibited RIG-I-mediated downstream signaling and antiviral activity. Knockdown of endogenous ARL16 by RNAi potentiated Sendai virus-induced IFN-β expression and vesicular stomatitis virus replication. ARL16 interacted with the C-terminal domain (CTD) of RIG-I to suppress the association between RIG-I and RNA. ARL16 (T37N) and ARL16Δ45-54, which were restricted to the GTP-disassociated form, did not interact with RIG-I and also lost the inhibitory function. Furthermore, we suggest that endogenous ARL16 changes to GTP binding status upon viral infection and binds with the RIG-I CTD to negatively control its signaling activity. These findings suggested a novel innate immune function for an ARL family member, and a GTP-dependent model in which RIG-I is regulated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / genetics
  • ADP-Ribosylation Factors / immunology
  • ADP-Ribosylation Factors / metabolism*
  • Amino Acid Sequence
  • Animals
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / immunology
  • DEAD-box RNA Helicases / metabolism*
  • Gene Expression Regulation / physiology
  • Guanosine Triphosphate / genetics
  • Guanosine Triphosphate / immunology
  • Guanosine Triphosphate / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Immunity, Innate / physiology
  • Interferon-beta / biosynthesis
  • Interferon-beta / genetics
  • Interferon-beta / immunology
  • Mice
  • Protein Structure, Tertiary
  • RNA, Viral / genetics
  • RNA, Viral / immunology
  • RNA, Viral / metabolism
  • Receptors, Immunologic
  • Sendai virus / genetics
  • Sendai virus / immunology
  • Sendai virus / metabolism
  • Sequence Deletion
  • Signal Transduction / physiology*

Substances

  • RNA, Viral
  • Receptors, Immunologic
  • Interferon-beta
  • Guanosine Triphosphate
  • RIGI protein, human
  • Ddx58 protein, mouse
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • ADP-Ribosylation Factors