Stimulation of immunity-linked genes by membrane disruption is linked to Golgi function and the ARF-1 GTPase

Abstract

SummaryImmune-linked genes (ILGs) are activated in response to pathogens but can also be activated by lipid imbalance. Why pathogen attack and metabolic changes both impact ILG activation is unclear. Organelles in the secretory pathway have distinct protein and lipid components and genetically separable stress programs. These stress pathways activate restorative transcriptional programs when lipid ratios become unbalanced or during dysregulated protein folding and trafficking. We find that ILGs are specifically activated when membrane phosphatidylcholine ratios change in the secretory pathway. Consistent with this result, disruption of Golgi function after RNAi targeting the ADP-ribosylation factor ARF-1 also activates ILG expression. Since increased protein secretion is altered by metabolic changes and pathogen responses, our data argue that ILG upregulation is a conserved, coordinated response to changes in trafficking resulting from intrinsic cues (lipid changes) or extrinsic stimulation (during the immune response). These findings uncover important and previously unexplored links between metabolism and the stress response.