SON DNA-binding protein mediates macrophage autophagy and responses to intracellular infection

FEBS Lett. 2020 Sep;594(17):2782-2799. doi: 10.1002/1873-3468.13851. Epub 2020 Jun 19.

Abstract

Intracellular pathogens affect diverse host cellular defence and metabolic pathways. Here, we used infection with Francisella tularensis to identify SON DNA-binding protein as a central determinant of macrophage activities. RNAi knockdown of SON increases survival of human macrophages following F. tularensis infection or inflammasome stimulation. SON is required for macrophage autophagy, interferon response factor 3 expression, type I interferon response and inflammasome-associated readouts. SON knockdown has gene- and stimulus-specific effects on inflammatory gene expression. SON is required for accurate splicing and expression of GBF1, a key mediator of cis-Golgi structure and function. Chemical GBF1 inhibition has similar effects to SON knockdown, suggesting that SON controls macrophage functions at least in part by controlling Golgi-associated processes.

Keywords: Francisella tularensis; autophagy; gene expression; host-pathogen interactions; inflammasome; interferon response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Autophagy / drug effects
  • Autophagy / genetics*
  • Cell Death
  • Cell Differentiation / drug effects
  • Cell Line
  • Cell Survival
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / immunology
  • Francisella tularensis / genetics
  • Francisella tularensis / immunology
  • Francisella tularensis / pathogenicity*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Golgi Apparatus / immunology*
  • Golgi Apparatus / metabolism
  • Golgi Apparatus / microbiology
  • Guanine Nucleotide Exchange Factors / antagonists & inhibitors
  • Guanine Nucleotide Exchange Factors / genetics*
  • Guanine Nucleotide Exchange Factors / immunology
  • Host-Pathogen Interactions / genetics*
  • Host-Pathogen Interactions / immunology
  • Humans
  • Inflammasomes / immunology
  • Inflammasomes / metabolism
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / immunology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Minor Histocompatibility Antigens / genetics*
  • Minor Histocompatibility Antigens / immunology
  • Pyridines / pharmacology
  • Quinolines / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • THP-1 Cells
  • Tetradecanoylphorbol Acetate / pharmacology

Substances

  • DNA-Binding Proteins
  • GBF1 protein, human
  • Guanine Nucleotide Exchange Factors
  • IRF3 protein, human
  • Inflammasomes
  • Interferon Regulatory Factor-3
  • Minor Histocompatibility Antigens
  • Pyridines
  • Quinolines
  • RNA, Small Interfering
  • SON protein, human
  • golgicide A
  • Tetradecanoylphorbol Acetate