Sensing of invading pathogens by GBPs: At the crossroads between cell-autonomous and innate immunity

Santos, José Carlos; Brož, Petr

doi:10.1002/jlb.4mr0118-038r

Cited by 55 publications

(52 citation statements)

References 57 publications

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“…The high degree of conservation in GBP1 and GBP2 CaaX boxes suggests that post-translational prenylation and subsequent membrane association has been critical for the function of both proteins. These findings agree with numerous studies illustrating how these GBPs are able to associate with diverse intracellular membranes that include pathogen-containing vacuoles, such as those occupied by the bacterium Chlamydia or the protist Toxoplasma, viral replication complexes and bacterial cell envelopes (5,25,26) . By first associating with these target membranes, GBP1 and GBP2 are able to recruit other GBP family members as well as additional immune effectors such as the immunity related GTPases (27) .…”

Section: Discussionsupporting

confidence: 92%

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A rapidly evolving polybasic motif modulates bacterial detection by guanylate binding proteins

Köhler

Kutsch

Piro

et al. 2019

Preprint

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Cell-autonomous immunity relies on the rapid detection of invasive pathogens by host proteins. Guanylate binding proteins (GBPs) have emerged as key mediators of vertebrate immune defense through their ability to recognize a diverse array of intracellular pathogens and pathogen-containing cellular compartments. Human and mouse GBPs have been shown to target distinct groups of microbes, although the molecular determinants of pathogen specificity remain unclear. We show that rapid diversification of a C-terminal polybasic motif (PBM) in primate GBPs controls recognition of the model cytosolic bacterial pathogen Shigella flexneri . By swapping this membrane-binding motif between primate GBP orthologs, we find that the ability to target S. flexneri has been enhanced and lost in specific lineages of New World monkeys. Single substitutions in rapidly evolving sites of the GBP1 PBM are sufficient to abolish or restore bacterial detection abilities, illustrating a role for epistasis in the evolution of pathogen recognition. We further demonstrate that the squirrel monkey GBP2 C-terminal domain recently gained the ability to target S. flexneri through a stepwise process of convergent evolution. These findings reveal a mechanism by which accelerated evolution of a PBM shifts GBP target specificity and aid in resolving the molecular basis of GBP function in cell-autonomous immune defense.

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Section: Discussionsupporting

confidence: 92%

“…Among the most highly-upregulated ISGs are a class of dynamin-related cytoplasmic GTPases called guanylate binding proteins, or GBPs. Vertebrate GBPs contribute to defense against diverse pathogens, and GBP function has also been implicated in the regulation of inflammation (3)(4)(5) .…”

Section: Introductionmentioning

confidence: 99%

A rapidly evolving polybasic motif modulates bacterial detection by guanylate binding proteins

Köhler

Kutsch

Piro

et al. 2019

Preprint

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“…However, it is not yet clear which type I IFN-inducible factors are responsible. Some recent reports (reviewed in [45][46][47]) suggest that intracellular membrane modifications such as viral ROs can be recognized and targeted by guanylate-binding proteins (GBPs), a family of dynamin-related large GTPases, of which DOI: 10.1159/000503030…”

Section: Attack Of the Replication Organelles By The Innate Immune Symentioning

confidence: 99%

Innate Immune Evasion by Human Respiratory RNA Viruses

2019

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The impact of respiratory virus infections on the health of children and adults can be very significant. Yet, in contrast to most other childhood infections as well as other viral and bacterial diseases, prophylactic vaccines or effective antiviral treatments against viral respiratory infections are either still not available, or provide only limited protection. Given the widespread prevalence, a general lack of natural sterilizing immunity, and/or high morbidity and lethality rates of diseases caused by influenza, respiratory syncytial virus, coronaviruses, and rhinoviruses, this difficult situation is a genuine societal challenge. A thorough understanding of the virushost interactions during these respiratory infections will most probably be pivotal to ultimately meet these challenges. This review attempts to provide a comparative overview of the knowledge about an important part of the interaction between respiratory viruses and their host: the arms race between host innate immunity and viral innate immune eva-

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“…The guanylate binding protein (GBP) family of cytosolic GTPases are among the most highly expressed proteins in macrophages exposed to IFNγ. The GBP protein family consists of seven members in the human and is involved in defence against bacterial, parasitic and viral intracellular pathogens, regulation of inflammasome signalling and cell death (Shenoy et al, 2012;Man et al, 2017;Santos & Broz, 2018;Gomes et al, 2019). All seven human GBPs possess an Nterminal, globular GTPase domain and a C-terminal helical domain which facilitates membrane interaction.…”

Section: Introductionmentioning

confidence: 99%

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

Fisch

Clough

Domart

et al. 2019

Preprint

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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.

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Sensing of invading pathogens by GBPs: At the crossroads between cell-autonomous and innate immunity

Cited by 55 publications

References 57 publications

A rapidly evolving polybasic motif modulates bacterial detection by guanylate binding proteins

A rapidly evolving polybasic motif modulates bacterial detection by guanylate binding proteins

Innate Immune Evasion by Human Respiratory RNA Viruses

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

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