PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection
Daniel Fisch, Moritz M. Pfleiderer, Eleni Anastasakou, Gillian M. Mackie, Fabian Wendt, Xiangyang Liu, Barbara Clough, Samuel Lara‐Reyna, Vesela Encheva, Ambrosius P. Snijders, Hironori Bando, Masahiro Yamamoto, Andrew D. Beggs, Jason Mercer, Avinash R. Shenoy, Bernd Wollscheid, Kendle M. Maslowski, Wojciech P. Galej, Eva‐Maria Frickel
Abstract
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.