PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection

Disruption of cellular activities by pathogen virulence factors can trigger innate immune responses. Interferon-gamma (IFNγ)-inducible antimicrobial factors, such as the guanylate binding proteins (GBPs), promote cell-intrinsic defense by attacking intracellular pathogens and by inducing programmed cell death. Working in human macrophages, we discovered that GBP1-expression in the absence of IFNγ killed the cells and induced Golgi fragmentation. IFNγ-exposure improved macrophage survival via the activity of the kinase PIM1. PIM1 phosphorylated GBP1 leading to its sequestration by 14-3-3σ, which thereby prevented GBP1 membrane association. During Toxoplasma gondii infection, the virulence protein TgIST interfered with IFNγ-signaling and depleted PIM1 thereby increasing GBP1-activity. While infected cells can restrain pathogens in a GBP1-dependent manner, this mechanism can protect uninfected bystander cells. Thus, PIM1 can provide a bait for pathogen virulence factors, guarding the integrity of IFNγ-signaling.