Ufm1 conjugation system inhibits interferon-γ activation of macrophages

Macrophages stimulated with interferon-γ (IFN-γ) in combination with tumor necrosis factor-α (TNFα) or lipopolysaccharide (LPS) respond with transcriptional and cellular changes that enhance clearance of intracellular pathogens but that may damage tissues. IFN-γ effects must therefore be carefully balanced with inhibitory mechanisms to prevent immunopathology. We performed a genome-wide CRISPR knockout screen to identify negative regulators of IFN-γ responses. We identified an unexpected role of the ubiquitin-fold modifier (Ufm1) conjugation system in inhibiting responses to IFN-γ and LPS. Enhanced IFN-γ activation in Ufm1-conjugation system-deficient cells resulted in increased transcriptional responses to IFN-γ, increased antiviral effects of IFN-γ and required ER stress responses dependent on Ern1 and Xbp1. These data link the Ufm1-conjugation machinery, ER homeostasis and the pro-inflammatory effects of IFN-γ.