A Cluster of Interferon-γ-Inducible p65 GTPases Plays a Critical Role in Host Defense against Toxoplasma gondii

Yamamoto, Masahiro; Okuyama, Masatsugu; Su, Ji Guo; Kimura, Taishi; Kamiyama, Naganori; Saiga, Hiroyuki; Ohshima, Jun; Sasai, Miwa; Kayama, Hisako; Okamoto, Tomoyoshi; Huang, David C.S.; Soldati‐Favre, Dominique; Horie, Kyoji; Takeda, Kiyoshi

doi:10.1016/j.immuni.2012.06.009

Cited by 288 publications

(367 citation statements)

References 51 publications

Supporting

Mentioning

357

Contrasting

Unclassified

Order By: Relevance

“…GBPs exert their antimicrobial and proinflammatory activities in part by binding to and disrupting PV membranes (5,6). Additionally, GBPs can translocate to cytoplasmic bacterial pathogens, where they induce bacteriolysis (8,12).…”

Section: Discussionmentioning

confidence: 99%

“…In IRGMdeficient cells, however, GKS proteins enter the active state prematurely, form protein aggregates, mislocalize, and thus fail to bind to PVs (17,21). Although these previous observations help explain how IRGM proteins promote the delivery of GKS proteins to PVs, IRGM proteins also control the subcellular localization of GBPs through an uncharacterized mechanism (6,17,(24)(25)(26).…”

Section: Significancementioning

confidence: 94%

“…Critical mediators of host-directed attacks on PVs are two families of IFNγ-inducible GTPases: immunityrelated GTPases (IRGs) and guanylate binding proteins (GBPs) (2). Members of both GTPase families play roles in host-mediated lysis of PVs, a process resulting in the release of microbes into the host cell cytoplasm, subsequent killing of PV-expelled microbes, and host cell death (3)(4)(5)(6)(7)(8). Additionally, GBPs help deliver cytosolic subunits of the antimicrobial NADPH oxidase NOX2 for assembly on phagosomal membranes, orchestrate the capture of PV-resident microbes inside degradative autophagolysosomes, and promote the activation of canonical and noncanonical inflammasome pathways (5,(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

See 2 more Smart Citations

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.

142

237

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 94%

mentioning

confidence: 99%

See 1 more Smart Citation

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.

142

237

View full text Add to dashboard Cite

show abstract

“…To test whether other GBPs might contribute to inflammasome activation by Yersinia translocon components, we infected BMDMs from Gbp Chr3Ϫ/Ϫ mice, which lack all five GBPs encoded on chromosome 3 (64) and are defective for inflammasome activation in response to cytoplasmic LPS, as well as cytosolic bacteria (28). Critically, BMDMs lacking all 5 GBPs encoded on chromosome 3 exhibited decreased cytotoxicity and secretion of both IL-1␤ and IL-1␣ in response to YopK-deficient Yersinia, whereas the secretion of an inflammasome-independent cytokine, IL-6, was unaffected ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

et al. 2017

Self Cite

View full text Add to dashboard Cite

Gram-negative bacterial pathogens utilize virulence-associated secretion systems to inject, or translocate, effector proteins into host cells to manipulate cellular processes and promote bacterial replication. However, translocated bacterial products are sensed by nucleotide binding domain and leucine-rich repeat-containing proteins (NLRs), which trigger the formation of a multiprotein complex called the inflammasome, leading to secretion of interleukin-1 (IL-1) family cytokines, pyroptosis, and control of pathogen replication. Pathogenic Yersinia bacteria inject effector proteins termed Yops, as well as pore-forming proteins that comprise the translocon itself, into target cells. The Yersinia translocation regulatory protein YopK promotes bacterial virulence by limiting hyperinjection of the translocon proteins YopD and YopB into cells, thereby limiting cellular detection of Yersinia virulence activity. How hyperinjection of translocon proteins leads to inflammasome activation is currently unknown. We found that translocated YopB and YopD colocalized with the late endosomal/lysosomal protein LAMP1 and that the frequency of YopD and LAMP1 association correlated with the level of caspase-1 activation in individual cells. We also observed colocalization between YopD and Galectin-3, an indicator of endosomal membrane damage. Intriguingly, YopK limited the colocalization of Galectin-3 with YopD, suggesting that YopK limits the induction or sensing of endosomal membrane damage by components of the type III secretion system (T3SS) translocon. Furthermore, guanylate binding proteins (GBPs) encoded on chromosome 3 (Gbp Chr3 ), which respond to pathogen-induced damage or alteration of host membranes, were necessary for inflammasome activation in response to hyperinjected YopB/-D. Our findings indicate that lysosomal damage by Yersinia translocon proteins promotes inflammasome activation and implicate GBPs as key regulators of this process.

show abstract

“…This targets the organism to autolysosomes and, thus, confers cell-autonomous host defense (48). Most interestingly, GBPs functionally cooperate with different members of the p47 GTPase family (60,61), which are thought to induce interaction of chlamydial structures with autophagosomes to reroute the pathogen to autolysosomes (62). For cargo degradation by cathepsins (63,64), autophagosomes fuse with endosomes to form multivesicular amphisomes (44).…”

Section: Discussionmentioning

confidence: 99%

Amphisomal Route of MHC Class I Cross-Presentation in Bacteria-Infected Dendritic Cells

Fiegl

Kägebein

Liebler-Tenorio

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Dendritic cells (DCs) are among the first professional APCs encountered by the obligate intracellular bacterium Chlamydia during infection. Using an established mouse bone marrow–derived DC line, we show that DCs control chlamydial infection in multiple small inclusions characterized by restricted bacterial growth, impaired cytosolic export of the virulence factor chlamydial protease–like activity factor, and interaction with guanylate-binding protein 1, a host cell factor involved in the initiation of autophagy. During maturation of infected DCs, chlamydial inclusions disintegrate, likely because they lack chlamydial protease–like activity factor–mediated protection. Released cytosolic Chlamydia are taken up by autophagosomes and colocalize with cathepsin-positive amphisomal vacuoles, to which peptide transporter TAP and upregulated MHC class I (MHC I) are recruited. Chlamydial Ags are subsequently generated through routes involving preprocessing in amphisomes via cathepsins and entry into the cytosol for further processing by the proteasome. Finally, bacterial peptides are reimported into the endosomal pathway for loading onto recycling MHC I. Thus, we unravel a novel pathway of MHC I–mediated cross-presentation that is initiated with a host cellular attack physically disrupting the parasitophorous vacuole, involves autophagy to collect cytosolic organisms into autophagosomes, and concludes with complex multistep antigenic processing in separate cellular compartments.

show abstract

A Cluster of Interferon-γ-Inducible p65 GTPases Plays a Critical Role in Host Defense against Toxoplasma gondii

Cited by 288 publications

References 51 publications

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

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

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

Amphisomal Route of MHC Class I Cross-Presentation in Bacteria-Infected Dendritic Cells

Contact Info

Product

Resources

About