PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection PMID: 37797010

GLP-1 and Obesity Research

2026-08-18

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

Science. 2023 Oct 6;382(6666):eadg2253. doi: 10.1126/science.adg2253.

Daniel Fisch ¹ ² , Moritz M Pfleiderer ³ , Eleni Anastasakou ³ , Gillian M Mackie ⁴ , Fabian Wendt ⁵ ⁶ , Xiangyang Liu ³ , Barbara Clough ² , Samuel Lara-Reyna ² , Vesela Encheva ⁷ , Ambrosius P Snijders ⁷ ⁸ , Hironori Bando ⁹ ¹⁰ , Masahiro Yamamoto ⁹ ¹⁰ , Andrew D Beggs ¹¹ , Jason Mercer ² , Avinash R Shenoy ¹² ¹³ , Bernd Wollscheid ⁵ ⁶ , Kendle M Maslowski ⁴ ¹⁴ ¹⁵ ¹⁶ , Wojtek P Galej ³ , Eva-Maria Frickel ¹ ²

Affiliations

1. Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, London, UK.
2. Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, UK.
3. European Molecular Biology Laboratory, 71 Avenue des Martyrs, Grenoble, France.
4. Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, UK.
5. Department of Health Sciences and Technology (D-HEST), ETH Zürich, Institute of Translational Medicine (ITM), Zürich, Switzerland.
6. Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
7. Mass Spectrometry and Proteomics Platform, The Francis Crick Institute, London, UK.
8. Bruker Nederland BV, Leiderdorp, Netherlands.
9. Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
10. Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
11. Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, UK.
12. MRC Centre for Molecular Bacteriology and Infection, Department of Infectious Disease, Imperial College London, London, UK.
13. Inflammasome Biology Laboratory, The Francis Crick Institute, London, UK.
14. Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, UK.
15. Cancer Research UK Beatson Institute, Glasgow, UK.
16. School of Cancer Sciences, University of Glasgow, Glasgow, UK.

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.