Human Guanylate Binding Proteins Potentiate the Anti-Chlamydia Effects of Interferon-γ

Tietzel, Illya; El-Haibi, Christelle P; Carabeo, Rey A.

doi:10.1371/journal.pone.0006499

Cited by 96 publications

(102 citation statements)

References 47 publications

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“…Overexpression of marker proteins such as Rab5, Rab7, or Rab9 enhanced this colocalization. Other groups have already identified certain GBPs on phagocytosed latex bead (42,43) and bacteria (44,45). In some cases, we observed recruitment of hGBP1 very early during formation of phagocytic cups.…”

Section: Discussionsupporting

confidence: 63%

Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1

Shydlovskyi

Zienert

İnce

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

120

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Dynamin-like proteins (DLPs) mediate various membrane fusion and fission processes within the cell, which often require the polymerization of DLPs. An IFN-inducible family of DLPs, the guanylate-binding proteins (GBPs), is involved in antimicrobial and antiviral responses within the cell. Human guanylate-binding protein 1 (hGBP1), the founding member of GBPs, is also engaged in the regulation of cell adhesion and migration. Here, we show how the GTPase cycle of farnesylated hGBP1 (hGBP1F) regulates its self-assembly and membrane interaction. Using vesicles of various sizes as a lipid bilayer model, we show GTP-dependent membrane binding of hGBP1F. In addition, we demonstrate nucleotide-dependent tethering ability of hGBP1F. Furthermore, we report nucleotide-dependent polymerization of hGBP1F, which competes with membrane binding of the protein. Our results show that hGBP1F acts as a nucleotide-controlled molecular switch by modulating the accessibility of its farnesyl moiety, which does not require any supportive proteins.

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Section: Discussionsupporting

confidence: 63%

Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1

Shydlovskyi

Zienert

İnce

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

120

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“…Another subset of GTPases, the p65 guanylate-binding proteins, are strongly induced by IFN-␥ in both human and mouse hosts (65). In contrast to the p47 GTPases, this subset has been suggested to actually sensitize chlamydia to Trp starvation, possibly as a result of GTP depletion (128). This would be consistent with the effect of Trp limitation upon nucleotide import from the host, as discussed later.…”

Section: Dilemma Posed By Extreme Differences In Host Responses Of Humentioning

confidence: 55%

The AlternativeTranslational Profile That Underlies the Immune-Evasive State of Persistence in Chlamydiaceae Exploits Differential Tryptophan Contents of the Protein Repertoire

Xie

Bonner

et al. 2012

Microbiol Mol Biol Rev

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SUMMARY One form of immune evasion is a developmental state called “persistence” whereby chlamydial pathogens respond to the host-mediated withdrawal of l -tryptophan (Trp). A sophisticated survival mode of reversible quiescence is implemented. A mechanism has evolved which suppresses gene products necessary for rapid pathogen proliferation but allows expression of gene products that underlie the morphological and developmental characteristics of persistence. This switch from one translational profile to an alternative translational profile of newly synthesized proteins is proposed to be accomplished by maximizing the Trp content of some proteins needed for rapid proliferation (e.g., ADP/ATP translocase, hexose-phosphate transporter, phosphoenolpyruvate [PEP] carboxykinase, the Trp transporter, the Pmp protein superfamily for cell adhesion and antigenic variation, and components of the cell division pathway) while minimizing the Trp content of other proteins supporting the state of persistence. The Trp starvation mechanism is best understood in the human- Chlamydia trachomatis relationship, but the similarity of up-Trp and down-Trp proteomic profiles in all of the pathogenic Chlamydiaceae suggests that Trp availability is an underlying cue relied upon by this family of pathogens to trigger developmental transitions. The biochemically expensive pathogen strategy of selectively increased Trp usage to guide the translational profile can be leveraged significantly with minimal overall Trp usage by (i) regional concentration of Trp residue placements, (ii) amplified Trp content of a single protein that is required for expression or maturation of multiple proteins with low Trp content, and (iii) Achilles'-heel vulnerabilities of complex pathways to high Trp content of one or a few enzymes.

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“…S10). GBP translocation to T. gondii PVs and C. trachomatis inclusions has also been observed in humans cells (48,49), yet human cells do not encode GKS proteins (20). These combined observations pose the conundrum of explaining how human GBPs target PVs independently of GKS proteins.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins

Haldar

Foltz

Finethy

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

151

237

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Many microbes create and maintain pathogen-containing vacuoles (PVs) as an intracellular niche permissive for microbial growth and survival. The destruction of PVs by IFNγ-inducible guanylate binding protein (GBP) and immunity-related GTPase (IRG) host proteins is central to a successful immune response directed against numerous PV-resident pathogens. However, the mechanism by which IRGs and GBPs cooperatively detect and destroy PVs is unclear. We find that host cell priming with IFNγ prompts IRG-dependent association of Toxoplasma- and Chlamydia-containing vacuoles with ubiquitin through regulated translocation of the E3 ubiquitin ligase tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6). This initial ubiquitin labeling elicits p62-mediated escort and deposition of GBPs to PVs, thereby conferring cell-autonomous immunity. Hypervirulent strains of Toxoplasma gondii evade this process via specific rhoptry protein kinases that inhibit IRG function, resulting in blockage of downstream PV ubiquitination and GBP delivery. Our results define a ubiquitin-centered mechanism by which host cells deliver GBPs to PVs and explain how hypervirulent parasites evade GBP-mediated immunity.

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Human Guanylate Binding Proteins Potentiate the Anti-Chlamydia Effects of Interferon-γ

Cited by 96 publications

References 47 publications

Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1

Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1

The AlternativeTranslational Profile That Underlies the Immune-Evasive State of Persistence in Chlamydiaceae Exploits Differential Tryptophan Contents of the Protein Repertoire

Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins

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