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

• Published in: 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 American Association for the Advancement of Science (AAAS) 06.10.2023; The American Association for the Advancement of Science
• Subjects: 14-3-3 protein; 14-3-3 Proteins; 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; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; Guanylate-binding protein; Host-Pathogen Interactions; Host-Pathogen Interactions - immunology; Humans; Immunity, Innate; Infections; Inflammation; Innate immunity; Interferon; Interferon-gamma; 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; Proto-Oncogene Proteins c-pim-1 - metabolism; Self-injury; Toxoplasma; Toxoplasmosis; Toxoplasmosis - immunology; Vacuoles; Virulence Factors; 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 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. Mammalian cells use guard mechanisms to monitor their functional pathways for interference by pathogens. Infection causes the production of the inflammatory cytokine interferon-γ (IFN-γ), which triggers the expression of hundreds of IFN-stimulated-genes, including the kinase PIM1 and GBP1, a membrane-perturbing GTPase. Fisch et al . identified a guard mechanism whereby PIM1 phosphorylates GBP1 and subjects it to sequestration by a 14-3-3 protein. In human macrophages, this mechanism was found to prevent GBP1 activity from causing Golgi fragmentation and cell death. Pathogens can interfere with IFN-γ signaling and thereby potentially escape immune detection. However, when this signaling is inhibited, short-lived PIM1 is degraded, which allows GBP1 to control pathogen growth. These findings suggest a model of IFN-γ–dependent protection of uninfected bystander cells against self-inflicted innate immune damage. —Stella M. Hurtley Phosphorylation of an IFN-γ–induced protein protects IFN-γ signaling and promotes bystander cell protection in human macrophages.