Nuclear receptor ERRα and coactivator PGC-1β are effectors of IFN-γ-induced host defense

Junichiro Sonoda, Josée Laganière, Isaac R. Mehl, Grant D. Barish, Ling Wa Chong, Xiangli Li, Immo E. Scheffler, Dennis C. Mock, Alain R. Bataille, François Robert, Chih Hao Lee, Vincent Giguère*, Ronald M. Evans

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

163 Scopus citations

Abstract

Macrophage activation by the proinflammatory cytokine interferon-γ (IFN-γ) is a critical component of the host innate response to bacterial pathogenesis. However, the precise nature of the IFN-γ-induced activation pathway is not known. Here we show using genome-wide expression and chromatin-binding profiling that IFN-γ induces the expression of many nuclear genes encoding mitochondrial respiratory chain machinery via activation of the nuclear receptor ERRα (estrogen-related receptor α, NR3B1). Studies with macrophages lacking ERRα demonstrate that it is required for induction of mitochondrial reactive oxygen species (ROS) production and efficient clearance of Listeria monocytogenes (LM) in response to IFN-γ. As a result, mice lacking ERRα are susceptible to LM infection, a phenotype that is localized to bone marrow-derived cells. Furthermore, we found that IFN-γ-induced activation of ERRα depends on coactivator PGC-1β (peroxisome proliferator-activated receptor γ coactivator-1β), which appears to be a direct target for the IFN-γ/STAT-1 signaling cascade. Thus, ERRα and PGC-1β act together as a key effector of IFN-γ-induced mitochondrial ROS production and host defense.

Original languageEnglish (US)
Pages (from-to)1909-1920
Number of pages12
JournalGenes and Development
Volume21
Issue number15
DOIs
StatePublished - Aug 1 2007

Keywords

  • Listeria monocytogenes
  • Macrophages
  • Mitochondria
  • Oxidative metabolism
  • Reactive oxygen species

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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