PXD029463-1

PXD029463 is an original dataset announced via ProteomeXchange.

Title	PIM1 controls GBP1 activity to limit self-damage and guard against pathogen infection
Description	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.
HostingRepository	PRIDE
AnnounceDate	2023-07-26
AnnouncementXML	Submission_2023-07-26_10:45:40.143.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	DanielFisch
SpeciesList	scientific name: Toxoplasma gondii PRU; NCBI TaxID: 1080348; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-01 05:00:18	ID requested
⏵ 1	2023-07-26 10:45:40	announced
2	2024-10-22 05:58:09	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: PIM1, GBP1,Guanylate Binding Proteins, 14-3-3, host-pathogen interaction, bystander cells, cell intrinsic immunity

BramSnijders
contact affiliation	Head of Mass Spectrometry and Proteomics STP (lab head)
contact email	bram.snijders@crick.ac.uk
lab head
DanielFisch
contact affiliation	Boston Children's Hospital
contact email	daniel.fisch@crick.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD029463
     1. Label: PRIDE project
     2. Name: PIM1 controls GBP1 activity to limit self-damage and guard against pathogen infection