PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection
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 cel...
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| Published in | Science (American Association for the Advancement of Science) Vol. 382; no. 6666; p. eadg2253 |
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| Main Authors | , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
The American Association for the Advancement of Science
06.10.2023
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| Subjects | |
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| 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
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. |
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| AbstractList | Disruption of cellular activities by pathogen virulence factors can trigger innate immune responses. Interferon-gamma (IFNγ)-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 IFNγ killed the cells and induced Golgi fragmentation. IFNγ-exposure improved macrophage survival via 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 IFNγ-signaling and depleted PIM1 thereby increasing GBP1-activity. While 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 IFNγ-signaling. 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. 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. 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.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. Editor’s summaryMammalian 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. HurtleyINTRODUCTIONCells in infected tissues are exposed to inflammatory stimuli, including the innate and adaptive immunity–stimulating cytokine interferon-γ (IFN-γ). Although most tissue-resident and infiltrating cells are not infected, when exposed to IFN-γ, these bystander cells preemptively express a repertoire of interferon-stimulated genes (ISGs) with robust antimicrobial activities and the potential for self-harm. ISGs of the guanylate-binding protein (GBP) family are large, membrane-active guanosine triphosphatases (GTPases). GBPs can control intracellular microbes in various ways, most importantly by promoting membrane rupture and the release of microbial ligands and by the induction of programmed cell death, including pyroptosis and apoptosis. How uninfected cells protect themselves from the potentially self-destructive actions of GBPs while keeping these proteins readily available to combat infection is unknown.RATIONALECells need to tightly control the activity of antimicrobial proteins but rapidly deploy them upon infection. How is this achieved in human cells? Posttranslational modifications, such as phosphorylation by protein kinases, enable rapid and precise control of protein activities. We studied the phosphorylation of GBP1, a typical ISG, and how this modification affects its function, activity, and localization in human macrophages.RESULTSEctopic expression of GBP1 in human macrophages led to changes in cell morphology, GBP1 accumulation at the Golgi apparatus, Golgi fragmentation, and uncontrolled cellular necrosis. These findings illustrate GBP1’s potential to inflict self-damage. This phenotype was mitigated by IFN-γ treatment, suggesting that another IFN-γ–inducible factor limited GBP1 activity. We identified the kinase PIM1 as being this factor. We generated a phosphorylation-specific antibody and used high-resolution mass spectrometry to demonstrate GBP1 phosphorylation at serine-156 (Ser156), which was guided by a basophilic PIM1 recognition motif. Ser156 is the central residue of a 14-3-3 protein binding motif, which suggests a switch-like function for its phosphorylation. Indeed, 14-3-3 proteins, especially 14-3-3σ, interacted with phosphorylated GBP1. In vitro reconstitution of this complex followed by single-particle cryo–electron microscopy confirmed a 14-3-3σ dimer grabbing onto the GBP1 GTPase domain. This binding locked GBP1 in a GTPase-inactive, monomeric state and restrained its activity in the macrophage cytosol. Expressing phosphorylation-deficient GBP1 mutants or mutants that could not be recognized by the kinase PIM1 or bound by 14-3-3σ led to uncontrolled GBP1 activation and subsequent cell death. Genetic depletion of either PIM1 or 14-3-3σ had similar outcomes, as did treatment with the GBP1:PIM1 interaction inhibitor NSC756093. Using the inhibitor in IFN-γ–activated patient-derived tumor organoids increased organoid death and prevented organoid reformation. Thus, we found that PIM1 and 14-3-3σ together controlled the activity of GBP1 in human cells. Disrupting PIM1-driven control of GBP1 has potential therapeutic implications for cancer therapy and innate immunity.We observed that PIM1 mRNA and protein were extremely short-lived. Infection with the apicomplexan parasite Toxoplasma gondii, a pathogen that resides within intracellular vacuoles and blocks IFN-γ signaling by means of the effector protein TgIST, led to fast depletion of PIM1. This in turn reduced GBP1 Ser156 phosphorylation levels and liberated GBP1 from 14-3-3σ sequestration. High-throughput imaging revealed that GBP1 then rapidly targeted Toxoplasma-containing vacuoles to improve control of the infection.CONCLUSIONThe IFN-γ–induced, short-lived kinase PIM1 guards the integrity of IFN-γ signaling and protects self-membranes by regulating the activity of the potent antimicrobial effector GBP1. Pathogens that block IFN-γ signaling, thereby reducing the levels of PIM1, are then exposed to GBP1-driven innate immune control. The phosphoregulation of GBP1 by PIM1 reveals an IFN-γ–dependent control mechanism that protects uninfected bystander cells from self-inflicted innate immune damage during the process of pathogen elimination. |
| Author | Mercer, Jason Maslowski, Kendle M Frickel, Eva-Maria Shenoy, Avinash R Wollscheid, Bernd Snijders, Ambrosius P Anastasakou, Eleni Encheva, Vesela Fisch, Daniel Mackie, Gillian M Liu, Xiangyang Lara-Reyna, Samuel Clough, Barbara Yamamoto, Masahiro Galej, Wojtek P Beggs, Andrew D Bando, Hironori Wendt, Fabian Pfleiderer, Moritz M |
| AuthorAffiliation | 10 Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan 1 Host- Toxoplasma Interaction Laboratory, The Francis Crick Institute, London, UK 14 Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, UK 7 Mass Spectrometry and Proteomics Platform, The Francis Crick Institute, London, UK 11 Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, UK 16 School of Cancer Sciences, University of Glasgow, Glasgow, UK 15 Cancer Research UK Beatson Institute, Glasgow, UK 4 Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, UK 13 The Francis Crick Institute, London, UK 5 Department of Health Sciences and Technology (D-HEST), ETH Zurich, Institute of Translational Medicine (ITM), Zurich, Switzerland 8 Bruker Nederland BV 9 Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan 12 MRC Centre for Molecular Bacteriology & Infectio |
| AuthorAffiliation_xml | – name: 1 Host- Toxoplasma Interaction Laboratory, The Francis Crick Institute, London, UK – name: 14 Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, UK – name: 5 Department of Health Sciences and Technology (D-HEST), ETH Zurich, Institute of Translational Medicine (ITM), Zurich, Switzerland – name: 6 Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland – name: 7 Mass Spectrometry and Proteomics Platform, The Francis Crick Institute, London, UK – name: 8 Bruker Nederland BV – name: 15 Cancer Research UK Beatson Institute, Glasgow, UK – name: 12 MRC Centre for Molecular Bacteriology & Infection, Department of Infectious Disease, Imperial College London, London, UK – name: 11 Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, UK – name: 4 Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, UK – name: 3 European Molecular Biology Laboratory, 71 Avenue des Martyrs, Grenoble, France – name: 10 Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan – name: 9 Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan – name: 13 The Francis Crick Institute, London, UK – name: 2 Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, UK – name: 16 School of Cancer Sciences, University of Glasgow, Glasgow, UK |
| Author_xml | – sequence: 1 givenname: Daniel orcidid: 0000-0002-8155-0367 surname: Fisch fullname: Fisch, Daniel organization: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, UK – sequence: 2 givenname: Moritz M orcidid: 0000-0002-2369-5824 surname: Pfleiderer fullname: Pfleiderer, Moritz M organization: European Molecular Biology Laboratory, 71 Avenue des Martyrs, Grenoble, France – sequence: 3 givenname: Eleni orcidid: 0000-0002-0606-3382 surname: Anastasakou fullname: Anastasakou, Eleni organization: European Molecular Biology Laboratory, 71 Avenue des Martyrs, Grenoble, France – sequence: 4 givenname: Gillian M orcidid: 0000-0001-7758-6570 surname: Mackie fullname: Mackie, Gillian M organization: Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, UK – sequence: 5 givenname: Fabian orcidid: 0000-0002-2501-536X surname: Wendt fullname: Wendt, Fabian organization: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland – sequence: 6 givenname: Xiangyang surname: Liu fullname: Liu, Xiangyang organization: European Molecular Biology Laboratory, 71 Avenue des Martyrs, Grenoble, France – sequence: 7 givenname: Barbara orcidid: 0000-0002-3235-6170 surname: Clough fullname: Clough, Barbara organization: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, UK – sequence: 8 givenname: Samuel orcidid: 0000-0002-9986-5279 surname: Lara-Reyna fullname: Lara-Reyna, Samuel organization: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, UK – sequence: 9 givenname: Vesela surname: Encheva fullname: Encheva, Vesela organization: Mass Spectrometry and Proteomics Platform, The Francis Crick Institute, London, UK – sequence: 10 givenname: Ambrosius P orcidid: 0000-0002-5416-8592 surname: Snijders fullname: Snijders, Ambrosius P organization: Bruker Nederland BV, Leiderdorp, Netherlands – sequence: 11 givenname: Hironori surname: Bando fullname: Bando, Hironori organization: Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan – sequence: 12 givenname: Masahiro orcidid: 0000-0002-6821-2785 surname: Yamamoto fullname: Yamamoto, Masahiro organization: Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan – sequence: 13 givenname: Andrew D orcidid: 0000-0003-0784-2967 surname: Beggs fullname: Beggs, Andrew D organization: Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, UK – sequence: 14 givenname: Jason surname: Mercer fullname: Mercer, Jason organization: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, UK – sequence: 15 givenname: Avinash R orcidid: 0000-0001-6228-9303 surname: Shenoy fullname: Shenoy, Avinash R organization: Inflammasome Biology Laboratory, The Francis Crick Institute, London, UK – sequence: 16 givenname: Bernd orcidid: 0000-0002-3923-1610 surname: Wollscheid fullname: Wollscheid, Bernd organization: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland – sequence: 17 givenname: Kendle M orcidid: 0000-0003-1995-5424 surname: Maslowski fullname: Maslowski, Kendle M organization: School of Cancer Sciences, University of Glasgow, Glasgow, UK – sequence: 18 givenname: Wojtek P orcidid: 0000-0001-8859-5229 surname: Galej fullname: Galej, Wojtek P organization: European Molecular Biology Laboratory, 71 Avenue des Martyrs, Grenoble, France – sequence: 19 givenname: Eva-Maria orcidid: 0000-0002-9515-3442 surname: Frickel fullname: Frickel, Eva-Maria organization: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, UK |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/37797010$$D View this record in MEDLINE/PubMed |
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| Snippet | Disruption of cellular activities by pathogen virulence factors can trigger innate immune responses. Interferon-γ (IFN-γ)-inducible antimicrobial factors, such... Disruption of cellular activities by pathogen virulence factors can trigger innate immune responses. Interferon-γ (IFN-γ)–inducible antimicrobial factors, such... Editor’s summaryMammalian cells use guard mechanisms to monitor their functional pathways for interference by pathogens. Infection causes the production of the... Disruption of cellular activities by pathogen virulence factors can trigger innate immune responses. Interferon-gamma (IFNγ)-inducible antimicrobial factors,... |
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| Title | PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection |
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