Sweet host revenge: Galectins and GBPs join forces at broken membranes

Coers, Jörn

doi:10.1111/cmi.12793

Cited by 27 publications

(21 citation statements)

References 53 publications

(90 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Taken together, we have established mGBP7 as a novel and essential player in the intricate machinery of cell-autonomous immunity toward T. gondii infection. It remains to be elucidated whether similar observations can be transferred to bacterial infections, where mGBPs arise as crucial factors in the control of pathogens (29)(30)(31). These findings provide further important evidence for the concerted action of GBPs in host defense.…”

Section: Discussionmentioning

confidence: 72%

Essential Role of mGBP7 for Survival of Toxoplasma gondii Infection

Steffens

Beuter-Gunia

Kravets

et al. 2020

mBio

View full text Add to dashboard Cite

Members of the murine guanylate-binding protein family (mGBP) are induced by interferon gamma (IFN-γ) and have been shown to be important factors in cell-autonomous immunity toward the intracellular pathogen Toxoplasma gondii. Previously, we identified that mGBP2 mediates disruption of the parasitophorous vacuole membrane (PVM) and directly assaults the plasma membrane of the parasite. Here, we show that mGBP7-deficient mice are highly susceptible to T. gondii infection. This is demonstrated by the loss of parasite replication control, pronounced development of ascites, and death of the animals in the acute infection phase. Interestingly, live-cell microscopy revealed that mGBP7 recruitment to the PVM occurs after mGBP2 recruitment, followed by disruption of the PVM and T. gondii integrity and accumulation of mGBP7 inside the parasite. This study defines mGBP7 as a crucial effector protein in resistance to intracellular T. gondii. IMPORTANCE Guanylate-binding proteins (GBPs) are induced by the inflammatory cytokine interferon gamma (IFN-γ) and have been shown to be important factors in the defense of the intracellular pathogen Toxoplasma gondii. In previous studies, we showed that members of the mouse GBP family, such as mGBP2 and mGBP7, accumulate at the parasitophorous vacuole of T. gondii, which is the replicatory niche of the parasite. In this study, we show that mice deficient in mGBP7 succumb early after infection with T. gondii, showing a complete failure of resistance to the pathogen. On a molecular level, mGBP7 is found directly at the parasite, likely mediating its destruction.

show abstract

Section: Discussionmentioning

confidence: 72%

Essential Role of mGBP7 for Survival of Toxoplasma gondii Infection

Steffens

Beuter-Gunia

Kravets

et al. 2020

mBio

View full text Add to dashboard Cite

show abstract

“…Whether human GBP1 targets microbial vacuoles in macrophages is not known. Murine Gbps in general and human GBPs in some cell lines are recruited to bacterial and Tg vacuoles (Coers, ; Man et al , ; Saeij & Frickel, ; Santos & Broz, ). As we identified atypical apoptosis via GBP1 and AIM2, we asked whether GBP1 was recruited to Tg parasitophorous vacuoles (PVs) and whether this was required for apoptosis.…”

Section: Resultsmentioning

confidence: 99%

Human GBP 1 is a microbe‐specific gatekeeper of macrophage apoptosis and pyroptosis

et al. 2019

View full text Add to dashboard Cite

The guanylate binding protein (GBP) family of interferon‐inducible GTPases promotes antimicrobial immunity and cell death. During bacterial infection, multiple mouse Gbps, human GBP2, and GBP5 support the activation of caspase‐1‐containing inflammasome complexes or caspase‐4 which trigger pyroptosis. Whether GBPs regulate other forms of cell death is not known. The apicomplexan parasite Toxoplasma gondii causes macrophage death through unidentified mechanisms. Here we report that Toxoplasma‐induced death of human macrophages requires GBP1 and its ability to target Toxoplasma parasitophorous vacuoles through its GTPase activity and prenylation. Mechanistically, GBP1 promoted Toxoplasma detection by AIM2, which induced GSDMD‐independent, ASC‐, and caspase‐8‐dependent apoptosis. Identical molecular determinants targeted GBP1 to Salmonella‐containing vacuoles. GBP1 facilitated caspase‐4 recruitment to Salmonella leading to its enhanced activation and pyroptosis. Notably, GBP1 could be bypassed by the delivery of Toxoplasma DNA or bacterial LPS into the cytosol, pointing to its role in liberating microbial molecules. GBP1 thus acts as a gatekeeper of cell death pathways, which respond specifically to infecting microbes. Our findings expand the immune roles of human GBPs in regulating not only pyroptosis, but also apoptosis.

show abstract

“…Notably, GBP1 exclusively targeted cytosolic STm and did not contribute to their vacuolar escape. Equally, GBP1 detection of cytosolic STm was independent of recruitment of Gal-8, which belongs to a family of lectins that can detect vacuole rupture when luminal polysaccharides become exposed to the cytoplasm (Coers, 2017). Both GBP1 and Gal-8 were recruited to bacteria early during infection, and it has been suggested that GBP1 can bind endogenous sulphated lipids exposed to the cytoplasm (Bradfield, 2016).…”

Section: Discussionmentioning

confidence: 99%

Human GBP1 differentially targetsSalmonellaandToxoplasmato license recognition of microbial ligands and caspase-mediated death

Fisch

Clough

Domart

et al. 2019

Preprint

View full text Add to dashboard Cite

Human guanylate binding proteins (GBPs), a family of IFNγ-inducible GTPases, promote cell-intrinsic defence against pathogens and host cell death. We previously identified GBP1 as a mediator of cell death of human macrophages infected with Toxoplasma gondii (Tg) or Salmonella Typhimurium (STm). How GBP1 targets microbes for AIM2 activation during Tg infection and caspase-4 during STm infection remains unclear. Here, using correlative light and electron microscopy and EdU labelling of Tg-DNA, we reveal that GBP1-decorated parasitophorous vacuoles (PVs) lose membrane integrity and release Tg-DNA for detection by AIM2-ASC-CASP8. In contrast, differential staining of cytosolic and vacuolar STm revealed that GBP1 does not contribute to STm escape into the cytosol but decorates almost all cytosolic STm leading to the recruitment of caspase-4. Caspase-5, which can bind LPS and whose expression is upregulated by IFNγ, does not target STm pointing to a key role for caspase-4 in pyroptosis. We also uncover a regulatory mechanism involving the inactivation of GBP1 by its cleavage at Asp192 by caspase-1. Cells expressing non-cleavable GBP1 D192E therefore undergo higher caspase-4-driven pyroptosis during STm infection. Taken together, our comparative studies elucidate microbe-specific spatiotemporal roles of GBP1 in inducing cell death by leading to assembly and regulation of divergent caspase signalling platforms.

show abstract

Sweet host revenge: Galectins and GBPs join forces at broken membranes

Cited by 27 publications

References 53 publications

Essential Role of mGBP7 for Survival of Toxoplasma gondii Infection

Essential Role of mGBP7 for Survival of Toxoplasma gondii Infection

Human GBP 1 is a microbe‐specific gatekeeper of macrophage apoptosis and pyroptosis

Human GBP1 differentially targetsSalmonellaandToxoplasmato license recognition of microbial ligands and caspase-mediated death

Contact Info

Product

Resources

About