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

• 成果类型: Article
• 署名作者: 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
• 署名单位: Francis Crick Institute; University of Birmingham; European Molecular Biology Laboratory (EMBL); University of Birmingham; Swiss Federal Institutes of Technology Domain; ETH Zurich; Swiss Institute of Bioinformatics; Francis Crick Institute; University of Osaka; University of Osaka; University of Birmingham; Imperial College London; Francis Crick Institute; University of Birmingham; Beatson Institute; University of Glasgow
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8815
• DOI: 10.1126/science.adg2253
• 发表日期: 2023-10-06
• 页码: 67-+
• 关键词: guanylate-binding protein-1; substrate-specificity; nucleotide-binding; gamma; phosphorylation; expression; immunity; pyrin; identification; inactivation

摘要

Disruption of cellular activities by pathogen virulence factors can trigger innate immune responses. Interferon-gamma (IFN-gamma)-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-gamma killed the cells and induced Golgi fragmentation. IFN-gamma exposure improved macrophage survival through the activity of the kinase PIM1. PIM1 phosphorylated GBP1, leading to its sequestration by 14-3-3 sigma, which thereby prevented GBP1 membrane association. During Toxoplasma gondii infection, the virulence protein TgIST interfered with IFN-gamma 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-gamma signaling.