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

Daniel Fisch; Moritz M Pfleiderer; Eleni Anastasakou; Gillian M Mackie; Fabian Wendt; Xiangyang Liu; Barbara Clough; Samuel Lara-Reyna; Vesela Encheva; Ambrosius P Snijders; Hironori Bando; Masahiro Yamamoto; Andrew D Beggs; Jason Mercer; Avinash R Shenoy; Bernd Wollscheid; Kendle M Maslowski; Wojtek P Galej; Eva-Maria Frickel

doi:10.1126/science.adg2253

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

Daniel Fisch, Moritz M Pfleiderer, Eleni Anastasakou, Gillian M Mackie, Fabian Wendt, Xiangyang Liu, Barbara Clough, Samuel Lara-Reyna, Vesela Encheva, Ambrosius P Snijders, Hironori Bando, Masahiro Yamamoto, Andrew D Beggs, Jason Mercer, Avinash R Shenoy, Bernd Wollscheid, Kendle M Maslowski, Wojtek P Galej, Eva-Maria Frickel^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	eadg2253
Number of pages	15
Journal	Science
Volume	382
Issue number	6666
DOIs	https://doi.org/10.1126/science.adg2253
Publication status	Published - 6 Oct 2023

Bibliographical note

Funding:
This research was funded, in whole or in part, by The Wellcome Trust. D.F. was supported by a Boehringer Ingelheim Fonds PhD fellowship, a Human Frontier Science Program (HFSP) long-term postdoctoral fellowship (LT0006/2022-L), and an EMBO nonstipendiary postdoctoral fellowship (ALTF 491-2022). M.Y. acknowledges support from the Agency for Medical Research and Development (AMED) Strategic International Collaborative Research Program (JP20jm0210067), Research Program on Emerging and Re-emerging Infectious Diseases (JP20fk0108137), and Japanese Initiative for Progress of Research on Infectious Diseases for Global Epidemic (JP20wm0325010); and a Grant-in-Aid for Transformative Research Area (B) (20B304), for Scientific Research on Innovation Areas (19H04809), for Scientific Research (B) (18KK0226 and 18H02642), and for Scientific Research (A) (19H00970) from the Ministry of Education, Culture, Sports, Science and Technology, Fusion Oriented Research for Disruptive Science and Technology. J.M. was supported by the European Research Council (649101-UbiProPox) and by Core funding to MRC Laboratory for Molecular Cell Biology at University College London (MC_UU_00012/7). A.R.S. was supported by MRC grant MR/P022138/1. E.-M.F. received funding from Wellcome Trust Senior Research Fellowship 217202/Z/19/Z, MRC Research and Innovation Grant MR/V030930/1 (also to A.R.S.), MRC-AMED grant MR/T029323/1 (also to M.Y.), and core funding to the Francis Crick Institute by Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust (FC001076). K.M.M. acknowledges support from CRUK CEA grant C61638/A27112. A.D.B. is funded by a CRUK Advanced Clinician Scientist Award (C31641/A23923). The Grenoble Instruct-ERIC center (UAR 3518 CNRS-CEA-UGA-EMBL) within the Grenoble Partnership for Structural Biology is supported by FRISBI (ANR-10-INBS-0005-02) and GRAL, which are financed within the University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS (ANR-17-EURE-0003). A.P.S. received core funding to the Francis Crick Institute by Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust (FC001999).

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10.1126/science.adg2253

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Fisch, D., Pfleiderer, M. M., Anastasakou, E., Mackie, G. M., Wendt, F., Liu, X., Clough, B., Lara-Reyna, S., Encheva, V., Snijders, A. P., Bando, H., Yamamoto, M., Beggs, A. D., Mercer, J., Shenoy, A. R., Wollscheid, B., Maslowski, K. M., Galej, W. P., & Frickel, E.-M. (2023). PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection. Science, 382(6666), Article eadg2253. https://doi.org/10.1126/science.adg2253

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title = "PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection",

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.",

author = "Daniel Fisch and Pfleiderer, {Moritz M} and Eleni Anastasakou and Mackie, {Gillian M} and Fabian Wendt and Xiangyang Liu and Barbara Clough and Samuel Lara-Reyna and Vesela Encheva and Snijders, {Ambrosius P} and Hironori Bando and Masahiro Yamamoto and Beggs, {Andrew D} and Jason Mercer and Shenoy, {Avinash R} and Bernd Wollscheid and Maslowski, {Kendle M} and Galej, {Wojtek P} and Eva-Maria Frickel",

note = "Funding: This research was funded, in whole or in part, by The Wellcome Trust. D.F. was supported by a Boehringer Ingelheim Fonds PhD fellowship, a Human Frontier Science Program (HFSP) long-term postdoctoral fellowship (LT0006/2022-L), and an EMBO nonstipendiary postdoctoral fellowship (ALTF 491-2022). M.Y. acknowledges support from the Agency for Medical Research and Development (AMED) Strategic International Collaborative Research Program (JP20jm0210067), Research Program on Emerging and Re-emerging Infectious Diseases (JP20fk0108137), and Japanese Initiative for Progress of Research on Infectious Diseases for Global Epidemic (JP20wm0325010); and a Grant-in-Aid for Transformative Research Area (B) (20B304), for Scientific Research on Innovation Areas (19H04809), for Scientific Research (B) (18KK0226 and 18H02642), and for Scientific Research (A) (19H00970) from the Ministry of Education, Culture, Sports, Science and Technology, Fusion Oriented Research for Disruptive Science and Technology. J.M. was supported by the European Research Council (649101-UbiProPox) and by Core funding to MRC Laboratory for Molecular Cell Biology at University College London (MC_UU_00012/7). A.R.S. was supported by MRC grant MR/P022138/1. E.-M.F. received funding from Wellcome Trust Senior Research Fellowship 217202/Z/19/Z, MRC Research and Innovation Grant MR/V030930/1 (also to A.R.S.), MRC-AMED grant MR/T029323/1 (also to M.Y.), and core funding to the Francis Crick Institute by Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust (FC001076). K.M.M. acknowledges support from CRUK CEA grant C61638/A27112. A.D.B. is funded by a CRUK Advanced Clinician Scientist Award (C31641/A23923). The Grenoble Instruct-ERIC center (UAR 3518 CNRS-CEA-UGA-EMBL) within the Grenoble Partnership for Structural Biology is supported by FRISBI (ANR-10-INBS-0005-02) and GRAL, which are financed within the University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS (ANR-17-EURE-0003). A.P.S. received core funding to the Francis Crick Institute by Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust (FC001999).",

year = "2023",

month = oct,

day = "6",

doi = "10.1126/science.adg2253",

language = "English",

volume = "382",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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Fisch, D, Pfleiderer, MM, Anastasakou, E, Mackie, GM, Wendt, F, Liu, X, Clough, B, Lara-Reyna, S, Encheva, V, Snijders, AP, Bando, H, Yamamoto, M, Beggs, AD , Mercer, J, Shenoy, AR, Wollscheid, B, Maslowski, KM, Galej, WP & Frickel, E-M 2023, 'PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection', Science, vol. 382, no. 6666, eadg2253. https://doi.org/10.1126/science.adg2253

TY - JOUR

T1 - PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection

AU - Fisch, Daniel

AU - Pfleiderer, Moritz M

AU - Anastasakou, Eleni

AU - Mackie, Gillian M

AU - Wendt, Fabian

AU - Liu, Xiangyang

AU - Clough, Barbara

AU - Lara-Reyna, Samuel

AU - Encheva, Vesela

AU - Snijders, Ambrosius P

AU - Bando, Hironori

AU - Yamamoto, Masahiro

AU - Beggs, Andrew D

AU - Mercer, Jason

AU - Shenoy, Avinash R

AU - Wollscheid, Bernd

AU - Maslowski, Kendle M

AU - Galej, Wojtek P

AU - Frickel, Eva-Maria

N1 - Funding: This research was funded, in whole or in part, by The Wellcome Trust. D.F. was supported by a Boehringer Ingelheim Fonds PhD fellowship, a Human Frontier Science Program (HFSP) long-term postdoctoral fellowship (LT0006/2022-L), and an EMBO nonstipendiary postdoctoral fellowship (ALTF 491-2022). M.Y. acknowledges support from the Agency for Medical Research and Development (AMED) Strategic International Collaborative Research Program (JP20jm0210067), Research Program on Emerging and Re-emerging Infectious Diseases (JP20fk0108137), and Japanese Initiative for Progress of Research on Infectious Diseases for Global Epidemic (JP20wm0325010); and a Grant-in-Aid for Transformative Research Area (B) (20B304), for Scientific Research on Innovation Areas (19H04809), for Scientific Research (B) (18KK0226 and 18H02642), and for Scientific Research (A) (19H00970) from the Ministry of Education, Culture, Sports, Science and Technology, Fusion Oriented Research for Disruptive Science and Technology. J.M. was supported by the European Research Council (649101-UbiProPox) and by Core funding to MRC Laboratory for Molecular Cell Biology at University College London (MC_UU_00012/7). A.R.S. was supported by MRC grant MR/P022138/1. E.-M.F. received funding from Wellcome Trust Senior Research Fellowship 217202/Z/19/Z, MRC Research and Innovation Grant MR/V030930/1 (also to A.R.S.), MRC-AMED grant MR/T029323/1 (also to M.Y.), and core funding to the Francis Crick Institute by Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust (FC001076). K.M.M. acknowledges support from CRUK CEA grant C61638/A27112. A.D.B. is funded by a CRUK Advanced Clinician Scientist Award (C31641/A23923). The Grenoble Instruct-ERIC center (UAR 3518 CNRS-CEA-UGA-EMBL) within the Grenoble Partnership for Structural Biology is supported by FRISBI (ANR-10-INBS-0005-02) and GRAL, which are financed within the University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS (ANR-17-EURE-0003). A.P.S. received core funding to the Francis Crick Institute by Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust (FC001999).

PY - 2023/10/6

Y1 - 2023/10/6

N2 - 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.

AB - 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.

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U2 - 10.1126/science.adg2253

DO - 10.1126/science.adg2253

M3 - Article

C2 - 37797010

SN - 0036-8075

VL - 382

JO - Science

JF - Science

IS - 6666

M1 - eadg2253

ER -

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

Abstract

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