Regulation of Retinoic Acid Inducible Gene-I (RIG-I) Activation by the Histone Deacetylase 6

EBioMedicine. 2016 Jul;9:195-206. doi: 10.1016/j.ebiom.2016.06.015. Epub 2016 Jun 11.

Abstract

Retinoic acid inducible gene-I (RIG-I) is a cytosolic pathogen recognition receptor that initiates the immune response against many RNA viruses. Upon RNA ligand binding, RIG-I undergoes a conformational change facilitating its homo-oligomerization and activation that results in its translocation from the cytosol to intracellular membranes to bind its signaling adaptor protein, mitochondrial antiviral-signaling protein (MAVS). Here we show that RIG-I activation is regulated by reversible acetylation. Acetyl-mimetic mutants of RIG-I do not form virus-induced homo-oligomers, revealing that acetyl-lysine residues of the RIG-I repressor domain prevent assembly to active homo-oligomers. During acute infection, deacetylation of RIG-I promotes its oligomerization upon ligand binding. We identify histone deacetylase 6 (HDAC6) as the deacetylase that promotes RIG-I activation and innate antiviral immunity to recognize and restrict RNA virus infection.

Keywords: Deacetylation; HCV; HDAC6; Innate immunity; Interferon; RIG-I; West Nile virus.

MeSH terms

  • Acetylation / drug effects
  • Animals
  • Bufexamac / pharmacology
  • Cell Line
  • DEAD Box Protein 58 / antagonists & inhibitors
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / metabolism*
  • Genes, Reporter
  • HEK293 Cells
  • Hepacivirus / genetics
  • Hepacivirus / pathogenicity
  • Histone Deacetylase 6
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Immunity, Innate / drug effects
  • Immunoblotting
  • Interferon-beta / genetics
  • Interferon-beta / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects

Substances

  • RNA, Small Interfering
  • Bufexamac
  • Interferon-beta
  • Hdac6 protein, mouse
  • Histone Deacetylase 6
  • Histone Deacetylases
  • Ddx58 protein, mouse
  • DEAD Box Protein 58