Proteomics

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


ABSTRACT: Pathogen virulence factors interfere with various cellular activities, a disruption that can trigger innate immune responses. Interferon-gamma (IFNγ)-inducible antimicrobial factors, such as the guanylate binding proteins (GBPs), promote cell-intrinsic defense against intracellular pathogens by directly attacking intracellular pathogens and by committing the infected host cell to programmed cell death. GBPs are large GTPases that traffic to pathogens in the cytosol or that reside within membrane-bound compartments and restrict microbial growth. We discovered that ectopic expression of the prototypical IFNγ-inducible GTPase, Guanylate Binding Protein 1 (GBP1), in the absence of IFNγ kills human macrophages, accompanied by fragmentation of the Golgi apparatus. Exposure to IFNγ improved host cell survival via the activity of PIM1 kinase. PIM1 phosphorylates GBP1 and imposes its sequestration by 14-3-3σ to prevent membrane association of GBP1. Analysis by cryo-EM showed that a 14-3-3σ-dimer trapped GBP1 in an inactive monomeric state. This control mechanism becomes evident during Toxoplasma gondii infection, where the effector protein TgIST interferes with IFNγ-signaling and thereby unintentionally depletes the short-lived kinase PIM1. This, in turn, increases GBP1-driven control of the pathogen. Uninfected bystander cells are spared during inflammation, while the infected cells restrain the pathogen in a rapid GBP1-dependent manner. Our work establishes PIM1 as a bait for pathogen virulence factors, thus safeguarding the integrity of IFNγ-signaling. This work presents a new paradigm of IFNγ-dependent protection of uninfected cells against self-inflicted innate immune damage.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human) Toxoplasma Gondii Pru

TISSUE(S): Macrophage

DISEASE(S): Toxoplasmosis

SUBMITTER: Daniel Fisch  

LAB HEAD: Bram Snijders

PROVIDER: PXD029463 | Pride | 2023-07-26

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
Dataset_Annotation.txt Txt
THP-1_IFNg_CTRL1.raw Raw
THP-1_IFNg_CTRL2.raw Raw
THP-1_IFNg_CTRL3.raw Raw
THP-1_IFNg_Dox_DOX1.raw Raw
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