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

• Published in: Science (American Association for the Advancement of Science) Vol. 382; no. 6666; p. eadg2253
• Main Authors: Fisch, Daniel, Pfleiderer, Moritz M, Anastasakou, Eleni, Mackie, Gillian M, Wendt, Fabian, Liu, Xiangyang, Clough, Barbara, Lara-Reyna, Samuel, Encheva, Vesela, Snijders, Ambrosius P, Bando, Hironori, Yamamoto, Masahiro, Beggs, Andrew D, Mercer, Jason, Shenoy, Avinash R, Wollscheid, Bernd, Maslowski, Kendle M, Galej, Wojtek P, Frickel, Eva-Maria
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 06.10.2023
• Subjects: 14-3-3 protein; 14-3-3 Proteins - metabolism; Antibodies; Apoptosis; Cell activation; Cell death; Cell morphology; Cytokines; Cytology; Cytosol; Damage; Depletion; Electron microscopy; Exposure; Fragmentation; Genes; Golgi cells; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; Guanylate-binding protein; Guards; Host-Pathogen Interactions - immunology; Humans; Immunity, Innate; Infections; Inflammation; Innate immunity; Interferon; Interferon-gamma - metabolism; Intracellular; Intracellular signalling; Kinases; Literary Devices; Localization; Macrophages; Macrophages - immunology; Mammalian cells; Mass spectrometry; Mass spectroscopy; Membranes; Microorganisms; Mortality; mRNA; Mutants; Necrosis; Parasites; Pathogens; Phenotypes; Phosphorylation; Proteins; Proto-Oncogene Proteins c-pim-1 - metabolism; Self-injury; Toxoplasma; Toxoplasmosis - immunology; Vacuoles; Virulence Factors - metabolism; γ-Interferon
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adg2253

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 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.