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

doi:10.1101/gad.1553007

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

¹ Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA;
² Molecular Oncology Group, Departments of Medicine and Oncology, McGill University Health Centre, Montréal, Québec H3A 1A1, Canada;
³ Department of Biochemistry, McGill University, Montréal, Québec H3G 1Y6, Canada;
⁴ Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, San Francisco, California 94121, USA;
⁵ Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA;
⁶ Division of Biology, Molecular Biology Section, University of California, San Diego, La Jolla, California 92093 USA;
⁷ San Diego Supercomputer Center, University of California, San Diego, La Jolla, California 92093, USA;
⁸ Laboratory of Chromatin and Genomic Expression, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada;
⁹ Harvard School of Public Health, Department of Genetics and Complex Diseases, Boston, Massachusetts 02115, USA

↵10 These authors contributed equally to this work.

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.

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