PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infectionMore about Open Access at the Crick
Authors listDaniel Fisch Moritz M Pfleiderer Eleni Anastasakou Gillian M Mackie Fabian Wendt Xiangyang Liu Barbara Clough Samuel Lara-Reyna Vesela Encheva Bram Snijders Hironori Bando Masahiro Yamamoto Andrew D Beggs Jason Mercer Avinash R Shenoy Bernd Wollscheid Kendle M Maslowski Wojtek P Galej Eva-Maria Frickel
Disruption of cellular activities by pathogen virulence factors can trigger innate immune responses. Interferon-γ (IFN-γ)-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 IFN-γ killed the cells and induced Golgi fragmentation. IFN-γ exposure improved macrophage survival through 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 IFN-γ signaling and depleted PIM1, thereby increasing GBP1 activity. Although 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 IFN-γ signaling.
Issue number 6666