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• W3048774419 abstract "•Development of two microscopy assays for microbe/microbe-containing vacuole lysis•Human GBP1 is essential for the lysis of Toxoplasma gondii vacuoles and parasites•Caspase-4 recruitment, but not cytosolic escape of Salmonella, is GBP1 dependent•Caspase-1 cleaves and inactivates GBP1 and suppresses caspase-4-driven pyroptosis Interferon-inducible guanylate-binding proteins (GBPs) promote cell-intrinsic defense through host cell death. GBPs target pathogens and pathogen-containing vacuoles and promote membrane disruption for release of microbial molecules that activate inflammasomes. GBP1 mediates pyroptosis or atypical apoptosis of Salmonella Typhimurium (STm)- or Toxoplasma gondii (Tg)- infected human macrophages, respectively. The pathogen-proximal detection-mechanisms of GBP1 remain poorly understood, as humans lack functional immunity-related GTPases (IRGs) that assist murine Gbps. Here, we establish that GBP1 promotes the lysis of Tg-containing vacuoles and parasite plasma membranes, releasing Tg-DNA. In contrast, we show GBP1 targets cytosolic STm and recruits caspase-4 to the bacterial surface for its activation by lipopolysaccharide (LPS), but does not contribute to bacterial vacuole escape. Caspase-1 cleaves and inactivates GBP1, and a cleavage-deficient GBP1D192E mutant increases caspase-4-driven pyroptosis due to the absence of feedback inhibition. Our studies elucidate microbe-specific roles of GBP1 in infection detection and its triggering of the assembly of divergent caspase signaling platforms. Interferon-inducible guanylate-binding proteins (GBPs) promote cell-intrinsic defense through host cell death. GBPs target pathogens and pathogen-containing vacuoles and promote membrane disruption for release of microbial molecules that activate inflammasomes. GBP1 mediates pyroptosis or atypical apoptosis of Salmonella Typhimurium (STm)- or Toxoplasma gondii (Tg)- infected human macrophages, respectively. The pathogen-proximal detection-mechanisms of GBP1 remain poorly understood, as humans lack functional immunity-related GTPases (IRGs) that assist murine Gbps. Here, we establish that GBP1 promotes the lysis of Tg-containing vacuoles and parasite plasma membranes, releasing Tg-DNA. In contrast, we show GBP1 targets cytosolic STm and recruits caspase-4 to the bacterial surface for its activation by lipopolysaccharide (LPS), but does not contribute to bacterial vacuole escape. Caspase-1 cleaves and inactivates GBP1, and a cleavage-deficient GBP1D192E mutant increases caspase-4-driven pyroptosis due to the absence of feedback inhibition. Our studies elucidate microbe-specific roles of GBP1 in infection detection and its triggering of the assembly of divergent caspase signaling platforms. Most nucleated cells can defend themselves against infection by viruses, bacteria, and eukaryotic parasites in a process called cell-intrinsic immunity. These defense programs respond to the detection of pathogens by membrane-bound or cytosolic pattern recognition receptors (PRRs) (Jorgensen et al., 2017Jorgensen I. Rayamajhi M. Miao E.A. Programmed cell death as a defence against infection.Nat. Rev. Immunol. 2017; 17: 151-164Crossref PubMed Scopus (240) Google Scholar; MacMicking, 2012MacMicking J.D. Interferon-inducible effector mechanisms in cell-autonomous immunity.Nat. Rev. Immunol. 2012; 12: 367-382Crossref PubMed Scopus (257) Google Scholar; Mostowy and Shenoy, 2015Mostowy S. Shenoy A.R. The cytoskeleton in cell-autonomous immunity: structural determinants of host defence.Nat. Rev. Immunol. 2015; 15: 559-573Crossref PubMed Scopus (61) Google Scholar; Randow et al., 2013Randow F. MacMicking J.D. James L.C. Cellular self-defense: how cell-autonomous immunity protects against pathogens.Science. 2013; 340: 701-706Crossref PubMed Scopus (134) Google Scholar). In addition to antimicrobial molecules that restrict or kill pathogens, host cell-death is a destructive yet effective mechanism of defense since it removes replicative niches and traps intracellular pathogens within cell remnants (Jorgensen et al., 2016Jorgensen I. Zhang Y. Krantz B.A. Miao E.A. Pyroptosis triggers pore-induced intracellular traps (PITs) that capture bacteria and lead to their clearance by efferocytosis.J. Exp. Med. 2016; 213: 2113-2128Crossref PubMed Google Scholar). Antimicrobial immunity and cell death are enhanced by the type-II interferon (IFNγ), which induces the expression of up to 2,000 IFN-stimulated genes (ISGs) (MacMicking, 2012MacMicking J.D. Interferon-inducible effector mechanisms in cell-autonomous immunity.Nat. Rev. Immunol. 2012; 12: 367-382Crossref PubMed Scopus (257) Google Scholar; Schoggins, 2019Schoggins J.W. Interferon-stimulated genes: what do they all do?.Annu. Rev. Virol. 2019; 6: 567-584Crossref PubMed Scopus (38) Google Scholar). The guanylate-binding protein (GBP) family of GTPases, which are highly abundant in cells exposed to IFNγ, consists of seven members in the humans and eleven members in mice (Kresse et al., 2008Kresse A. Konermann C. Degrandi D. Beuter-Gunia C. Wuerthner J. Pfeffer K. Beer S. Analyses of murine GBP homology clusters based on in silico, in vitro and in vivo studies.BMC Genomics. 2008; 9: 158-170Crossref PubMed Scopus (0) Google Scholar; Olszewski et al., 2006Olszewski M.A. Gray J. Vestal D.J. In silico genomic analysis of the human and murine guanylate-binding protein (GBP) gene clusters.J. Interf. Cytokine. 2006; 352: 328-352Crossref Scopus (76) Google Scholar; Shenoy et al., 2007Shenoy A.R. Kim B.H. Choi H.P. Matsuzawa T. Tiwari S. MacMicking J.D. Emerging themes in IFN-γ-induced macrophage immunity by the p47 and p65 GTPase families.Immunobiology. 2007; 212: 771-784Crossref PubMed Scopus (0) Google Scholar, Shenoy et al., 2012Shenoy A.R. Wellington D.A. Kumar P. Kassa H. Booth C.J. Cresswell P. MacMicking J.D. GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals.Science. 2012; 336: 481-485Crossref PubMed Scopus (230) Google Scholar). GBPs target intracellular pathogens and mediate host-defense via autophagy, oxidative responses, inflammasomes, and cell death (Costa Franco et al., 2018Costa Franco M.M. Marim F. Guimarães E.S. Assis N.R.G. Cerqueira D.M. Alves-Silva J. Harms J. Splitter G. Smith J. Kanneganti T.-D. et al.Brucella abortus triggers a cGAS-independent STING pathway to induce host protection that involves guanylate-binding proteins and inflammasome activation.J. Immunol. 2018; 200: 607-622Crossref PubMed Scopus (18) Google Scholar; Feeley et al., 2017Feeley E.M. Pilla-Moffett D.M. Zwack E.E. Piro A.S. Finethy R. Kolb J.P. Martinez J. Brodsky I.E. Coers J. Galectin-3 directs antimicrobial guanylate binding proteins to vacuoles furnished with bacterial secretion systems.Proc. Natl. Acad. Sci. USA. 2017; 114: E1698-E1706Crossref PubMed Scopus (51) Google Scholar; Foltz et al., 2017Foltz C. Napolitano A. Khan R. Clough B. Hirst E.M. Frickel E.-M. TRIM21 is critical for survival of Toxoplasma gondii infection and localises to GBP-positive parasite vacuoles.Sci. Rep. 2017; 7: 5209Crossref PubMed Scopus (26) Google Scholar; Gomes et al., 2019Gomes M.T.R. Cerqueira D.M. Guimarães E.S. Campos P.C. Oliveira S.C. Guanylate-binding proteins at the crossroad of noncanonical inflammasome activation during bacterial infections.J. Leukoc. Biol. 2019; 106: 553-562Crossref PubMed Scopus (4) Google Scholar; Haldar et al., 2013Haldar A.K. Saka H.A. Piro A.S. Dunn J.D. Henry S.C. Taylor G.A. Frickel E.M. Valdivia R.H. Coers J. IRG and GBP host resistance factors target aberrant, “non-self” vacuoles characterized by the missing of “self” IRGM proteins.PLoS Pathog. 2013; 9: e1003414Crossref PubMed Scopus (97) Google Scholar, Haldar et al., 2014Haldar A.K. Piro A.S. Pilla D.M. Yamamoto M. Coers J. The E2-like conjugation enzyme Atg3 promotes binding of IRG and Gbp proteins to Chlamydia- and Toxoplasma-containing vacuoles and host resistance.PLoS ONE. 2014; 9: e86684Crossref PubMed Google Scholar, Haldar et al., 2015Haldar A.K. Foltz C. Finethy R. Piro A.S. Feeley E.M. Pilla-Moffett D.M. Komatsu M. Frickel E.-M. Coers J. Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins.Proc. Natl. Acad. Sci. USA. 2015; 112: E5628-E5637Crossref PubMed Scopus (80) Google Scholar; Kim et al., 2011Kim B.-H. Shenoy A.R. Kumar P. Das R. Tiwari S. MacMicking J.D. A family of IFN-γ-inducible 65-kD GTPases protects against bacterial infection.Science. 2011; 332: 717-721Crossref PubMed Scopus (277) Google Scholar, Kim et al., 2012Kim B.-H. Shenoy A.R. Kumar P. Bradfield C.J. MacMicking J.D. IFN-inducible GTPases in host cell defense.Cell Host Microbe. 2012; 12: 432-444Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar; Li et al., 2017Li P. Jiang W. Yu Q. Liu W. Zhou P. Li J. Xu J. Xu B. Wang F. Shao F. Ubiquitination and degradation of GBPs by a Shigella effector to suppress host defence.Nature. 2017; 551: 378-383Crossref PubMed Scopus (62) Google Scholar; Lindenberg et al., 2017Lindenberg V. Mölleken K. Kravets E. Stallmann S. Hegemann J.H. Degrandi D. Pfeffer K. Broad recruitment of mGBP family members to Chlamydia trachomatis inclusions.PLoS ONE. 2017; 12: e0185273Crossref PubMed Scopus (9) Google Scholar; Liu et al., 2018Liu B.C. Sarhan J. Panda A. Muendlein H.I. Ilyukha V. Coers J. Yamamoto M. Isberg R.R. Poltorak A. Constitutive interferon maintains GBP expression required for release of bacterial components upstream of pyroptosis and anti-DNA responses.Cell Rep. 2018; 24: 155-168.e5Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar; Man et al., 2015Man S.M. Karki R. Malireddi R.K.S. Neale G. Vogel P. Yamamoto M. Lamkanfi M. Kanneganti T.D. The transcription factor IRF1 and guanylate-binding proteins target activation of the AIM2 inflammasome by Francisella infection.Nat. Immunol. 2015; 16: 467-475Crossref PubMed Scopus (178) Google Scholar, Man et al., 2017Man S.M. Place D.E. Kuriakose T. Kanneganti T.-D. Interferon-inducible guanylate-binding proteins at the interface of cell-autonomous immunity and inflammasome activation.J. Leukoc. Biol. 2017; 101: 143-150Crossref PubMed Scopus (42) Google Scholar; Meunier et al., 2014Meunier E. Dick M.S. Dreier R.F. Schürmann N. Kenzelmann Broz D. Warming S. Roose-Girma M. Bumann D. Kayagaki N. Takeda K. et al.Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases.Nature. 2014; 509: 366-370Crossref PubMed Scopus (251) Google Scholar, Meunier et al., 2015Meunier E. Wallet P. Dreier R.F. Costanzo S. Anton L. Rühl S. Dussurgey S. Dick M.S. Kistner A. Rigard M. et al.Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida.Nat. Immunol. 2015; 16: 476-484Crossref PubMed Scopus (173) Google Scholar; Piro et al., 2017Piro A.S. Hernandez D. Luoma S. Feeley E.M. Finethy R. Yirga A. Frickel E.M. Lesser C.F. Coers J. Detection of cytosolic Shigella flexneri via a C-terminal triple-arginine motif of GBP1 inhibits actin-based motility.MBio. 2017; 8: e01979-17Crossref PubMed Scopus (30) Google Scholar; Santos et al., 2018Santos J.C. Dick M.S. Lagrange B. Degrandi D. Pfeffer K. Yamamoto M. Meunier E. Pelczar P. Henry T. Broz P. LPS targets host guanylate-binding proteins to the bacterial outer membrane for non-canonical inflammasome activation.EMBO J. 2018; 37: e98089Crossref PubMed Scopus (60) Google Scholar; Shenoy et al., 2012Shenoy A.R. Wellington D.A. Kumar P. Kassa H. Booth C.J. Cresswell P. MacMicking J.D. GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals.Science. 2012; 336: 481-485Crossref PubMed Scopus (230) Google Scholar; Tripal et al., 2007Tripal P. Bauer M. Naschberger E. Mörtinger T. Hohenadl C. Cornali E. Thurau M. Stürzl M. Unique features of different members of the human guanylate-binding protein family.J. Interf. Cytokine Res. 2007; 27: 44-52Crossref PubMed Scopus (0) Google Scholar; Wallet et al., 2017Wallet P. Benaoudia S. Mosnier A. Lagrange B. Martin A. Lindgren H. Golovliov I. Michal F. Basso P. Djebali S. et al.IFN-γ extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection.PLoS Pathog. 2017; 13: e1006630Crossref PubMed Scopus (19) Google Scholar; Wandel et al., 2017Wandel M.P. Pathe C. Werner E.I. Ellison C.J. Boyle K.B. von der Malsburg A. Rohde J. Randow F. GBPs inhibit motility of Shigella flexneri but are targeted for degradation by the bacterial ubiquitin ligase IpaH9.8.Cell Host Microbe. 2017; 22: 507-518.e5Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar; Zwack et al., 2017Zwack E.E. Feeley E.M. Burton A.R. Hu B. Yamamoto M. Kanneganti T.-D. Bliska J.B. Coers J. Brodsky I.E. Guanylate binding proteins regulate inflammasome activation in response to hyperinjected Yersinia translocon components.Infect. Immun. 2017; 85: e00778-e16Crossref Scopus (12) Google Scholar). Once GBPs translocate to a pathogen vacuole or the pathogen itself, they are thought to disrupt these membranes by an as yet uncharacterized mechanism (Kravets et al., 2016Kravets E. Degrandi D. Ma Q. Peulen T.-O.O. Klümpers V. Felekyan S. Kühnemuth R. Weidtkamp-Peters S. Seidel C.A. Pfeffer K. Guanylate binding proteins directly attack Toxoplasma gondii via supramolecular complexes.eLife. 2016; 5: e11479Crossref PubMed Google Scholar; Meunier et al., 2014Meunier E. Dick M.S. Dreier R.F. Schürmann N. Kenzelmann Broz D. Warming S. Roose-Girma M. Bumann D. Kayagaki N. Takeda K. et al.Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases.Nature. 2014; 509: 366-370Crossref PubMed Scopus (251) Google Scholar; Selleck et al., 2013Selleck E.M. Fentress S.J. Beatty W.L. Degrandi D. Pfeffer K. Virgin 4th, H.W. Macmicking J.D. Sibley L.D. Guanylate-binding protein 1 (Gbp1) contributes to cell-autonomous immunity against Toxoplasma gondii.PLoS Pathog. 2013; 9: e1003320Crossref PubMed Scopus (104) Google Scholar; Yamamoto et al., 2012Yamamoto M. Okuyama M. Ma J.S. Kimura T. Kamiyama N. Saiga H. Ohshima J. Sasai M. Kayama H. Okamoto T. et al.A cluster of interferon-γ-inducible p65 GTPases plays a critical role in host defense against Toxoplasma gondii.Immunity. 2012; 37: 302-313Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar). Disruption of barrier membranes leads to pathogen growth control and release of pathogen-associated molecular patterns (PAMPs), which are sensed by PRRs that can trigger host cell death. Whether GBPs directly recognize pathogen vacuolar membranes or PAMPs is an important question that has not yet been answered (Fisch et al., 2019aFisch D. Bando H. Clough B. Hornung V. Yamamoto M. Shenoy A.R. Frickel E.M. Human GBP1 is a microbe-specific gatekeeper of macrophage apoptosis and pyroptosis.EMBO J. 2019; 38: e100926Crossref PubMed Scopus (32) Google Scholar; Lagrange et al., 2018Lagrange B. Benaoudia S. Wallet P. Magnotti F. Provost A. Michal F. Martin A. Di Lorenzo F. Py B.F. Molinaro A. Henry T. Human caspase-4 detects tetra-acylated LPS and cytosolic Francisella and functions differently from murine caspase-11.Nat. Commun. 2018; 9: 242Crossref PubMed Scopus (43) Google Scholar; Meunier et al., 2014Meunier E. Dick M.S. Dreier R.F. Schürmann N. Kenzelmann Broz D. Warming S. Roose-Girma M. Bumann D. Kayagaki N. Takeda K. et al.Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases.Nature. 2014; 509: 366-370Crossref PubMed Scopus (251) Google Scholar; Pilla et al., 2014Pilla D.M. Hagar J.A. Haldar A.K. Mason A.K. Degrandi D. Pfeffer K. Ernst R.K. Yamamoto M. Miao E.A. Coers J. Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS.Proc. Natl. Acad. Sci. USA. 2014; 111: 6046-6051Crossref PubMed Scopus (175) Google Scholar; Santos et al., 2018Santos J.C. Dick M.S. Lagrange B. Degrandi D. Pfeffer K. Yamamoto M. Meunier E. Pelczar P. Henry T. Broz P. LPS targets host guanylate-binding proteins to the bacterial outer membrane for non-canonical inflammasome activation.EMBO J. 2018; 37: e98089Crossref PubMed Scopus (60) Google Scholar). A large body of work on GBPs has been carried out in murine cells, wherein these proteins closely collaborate with members of a second family of IFN-induced GTPases, comprising 23 members, the p47 immunity-related GTPases (IRGs) (Haldar et al., 2014Haldar A.K. Piro A.S. Pilla D.M. Yamamoto M. Coers J. The E2-like conjugation enzyme Atg3 promotes binding of IRG and Gbp proteins to Chlamydia- and Toxoplasma-containing vacuoles and host resistance.PLoS ONE. 2014; 9: e86684Crossref PubMed Google Scholar; Hunn et al., 2008Hunn J.P. Koenen-Waisman S. Papic N. Schroeder N. Pawlowski N. Lange R. Kaiser F. Zerrahn J. Martens S. Howard J.C. Regulatory interactions between IRG resistance GTPases in the cellular response to Toxoplasma gondii.EMBO J. 2008; 27: 2495-2509Crossref PubMed Scopus (106) Google Scholar; Khaminets et al., 2010Khaminets A. Hunn J.P. Könen-Waisman S. Zhao Y.O. Preukschat D. Coers J. Boyle J.P. Ong Y.-C.C. Boothroyd J.C. Reichmann G. Howard J.C. Coordinated loading of IRG resistance GTPases on to the Toxoplasma gondii parasitophorous vacuole.Cell. Microbiol. 2010; 12: 939-961Crossref PubMed Scopus (121) Google Scholar; Miyairi et al., 2007Miyairi I. Tatireddigari V.R.R.A. Mahdi O.S. Rose L.A. Belland R.J. Lu L. Williams R.W. Byrne G.I. The p47 GTPases Iigp2 and Irgb10 regulate innate immunity and inflammation to murine Chlamydia psittaci infection.J. Immunol. 2007; 179: 1814-1824Crossref PubMed Google Scholar; Shenoy et al., 2007Shenoy A.R. Kim B.H. Choi H.P. Matsuzawa T. Tiwari S. MacMicking J.D. Emerging themes in IFN-γ-induced macrophage immunity by the p47 and p65 GTPase families.Immunobiology. 2007; 212: 771-784Crossref PubMed Scopus (0) Google Scholar; Singh et al., 2006Singh S.B. Davis A.S. Taylor G.A. Deretic V. Human IRGM induces autophagy to eliminate intracellular mycobacteria.Science. 2006; 313: 1438-1441Crossref PubMed Scopus (684) Google Scholar, Singh et al., 2010Singh S.B. Ornatowski W. Vergne I. Naylor J. Delgado M. Roberts E. Ponpuak M. Master S. Pilli M. White E. et al.Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria.Nat. Cell Biol. 2010; 12: 1154-1165Crossref PubMed Scopus (163) Google Scholar; Tiwari et al., 2009Tiwari S. Choi H.P. Matsuzawa T. Pypaert M. MacMicking J.D. Targeting of the GTPase Irgm1 to the phagosomal membrane via PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3) promotes immunity to mycobacteria.Nat. Immunol. 2009; 10: 907-917Crossref PubMed Scopus (84) Google Scholar). For instance, mouse Irgb10 targets bacteria following mGbp recruitment and contributes to the release of bacterial LPS and DNA, and mouse Irgm1 and Irgm3 are essential regulators of mGbp-targeting of some pathogen-containing vacuoles (Haldar et al., 2015Haldar A.K. Foltz C. Finethy R. Piro A.S. Feeley E.M. Pilla-Moffett D.M. Komatsu M. Frickel E.-M. Coers J. Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins.Proc. Natl. Acad. Sci. USA. 2015; 112: E5628-E5637Crossref PubMed Scopus (80) Google Scholar; Man et al., 2016Man S.M. Karki R. Sasai M. Place D.E. Kesavardhana S. Temirov J. Frase S. Zhu Q. Malireddi R.K.S. Kuriakose T. et al.IRGB10 liberates bacterial ligands for sensing by the AIM2 and caspase-11-NLRP3 inflammasomes.Cell. 2016; 167: 382-396.e17Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar; Meunier et al., 2014Meunier E. Dick M.S. Dreier R.F. Schürmann N. Kenzelmann Broz D. Warming S. Roose-Girma M. Bumann D. Kayagaki N. Takeda K. et al.Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases.Nature. 2014; 509: 366-370Crossref PubMed Scopus (251) Google Scholar; Singh et al., 2010Singh S.B. Ornatowski W. Vergne I. Naylor J. Delgado M. Roberts E. Ponpuak M. Master S. Pilli M. White E. et al.Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria.Nat. Cell Biol. 2010; 12: 1154-1165Crossref PubMed Scopus (163) Google Scholar). However, only one constitutively expressed, truncated IRG, called “IRGM,” is present in the human genome (Bekpen et al., 2005Bekpen C. Hunn J.P. Rohde C. Parvanova I. Guethlein L. Dunn D.M. Glowalla E. Leptin M. Howard J.C. The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage.Genome Biol. 2005; 6: R92Crossref PubMed Google Scholar, Bekpen et al., 2010Bekpen C. Xavier R.J. Eichler E.E. Human IRGM gene “to be or not to be”.Semin. Immunopathol. 2010; 32: 437-444Crossref PubMed Scopus (21) Google Scholar). Therefore, how human GBPs target intracellular pathogens remains unknown. In addition, some PRRs are unique to humans, for example caspase-4 and caspase-5 (Casson et al., 2015Casson C.N. Yu J. Reyes V.M. Taschuk F.O. Yadav A. Copenhaver A.M. Nguyen H.T. Collman R.G. Shin S. Human caspase-4 mediates noncanonical inflammasome activation against gram-negative bacterial pathogens.Proc. Natl. Acad. Sci. USA. 2015; 112: 6688-6693Crossref PubMed Scopus (109) Google Scholar; Ding and Shao, 2017Ding J. Shao F. SnapShot: the noncanonical inflammasome.Cell. 2017; 168: 544-544.e1Abstract Full Text PDF PubMed Scopus (25) Google Scholar; Kayagaki et al., 2011Kayagaki N. Warming S. Lamkanfi M. Vande Walle L. Louie S. Dong J. Newton K. Qu Y. Liu J. Heldens S. et al.Non-canonical inflammasome activation targets caspase-11.Nature. 2011; 479: 117-121Crossref PubMed Scopus (1176) Google Scholar, Kayagaki et al., 2013Kayagaki N. Wong M.T. Stowe I.B. Ramani S.R. Gonzalez L.C. Akashi-Takamura S. Miyake K. Zhang J. Lee W.P. Muszyński A. et al.Noncanonical inflammasome activation by intracellular LPS independent of TLR4.Science. 2013; 341: 1246-1249Crossref PubMed Scopus (685) Google Scholar; Shi et al., 2014Shi J. Zhao Y. Wang Y. Gao W. Ding J. Li P. Hu L. Shao F. Inflammatory caspases are innate immune receptors for intracellular LPS.Nature. 2014; 514: 187-192Crossref PubMed Scopus (36) Google Scholar), which enable human, but not mouse cells, to respond to tetra-acylated LPS (Lagrange et al., 2018Lagrange B. Benaoudia S. Wallet P. Magnotti F. Provost A. Michal F. Martin A. Di Lorenzo F. Py B.F. Molinaro A. Henry T. Human caspase-4 detects tetra-acylated LPS and cytosolic Francisella and functions differently from murine caspase-11.Nat. Commun. 2018; 9: 242Crossref PubMed Scopus (43) Google Scholar). The mechanisms underlying GBP-mediated detection of pathogens and stimulation of human macrophage death therefore need to be investigated further. All seven human GBPs have a conserved structure with an N-terminal globular GTPase domain and a C-terminal helical domain. GBP1, GBP2, and GBP5 can be isoprenylated at their C-terminal CaaX-box, allowing membrane anchoring (Britzen-Laurent et al., 2010Britzen-Laurent N. Bauer M. Berton V. Fischer N. Syguda A. Reipschläger S. Naschberger E. Herrmann C. Stürzl M. Intracellular trafficking of guanylate-binding proteins is regulated by heterodimerization in a hierarchical manner.PLoS ONE. 2010; 5: e14246Crossref PubMed Scopus (61) Google Scholar; Nantais et al., 1996Nantais D.E. Schwemmle M. Stickney J.T. Vestal D.J. Buss J.E. Prenylation of an interferon-γ-induced GTP-binding protein: the human guanylate binding protein, huGBP1.J. Leukoc. Biol. 1996; 60: 423-431Crossref PubMed Scopus (44) Google Scholar; Olszewski et al., 2006Olszewski M.A. Gray J. Vestal D.J. In silico genomic analysis of the human and murine guanylate-binding protein (GBP) gene clusters.J. Interf. Cytokine. 2006; 352: 328-352Crossref Scopus (76) Google Scholar; Tripal et al., 2007Tripal P. Bauer M. Naschberger E. Mörtinger T. Hohenadl C. Cornali E. Thurau M. Stürzl M. Unique features of different members of the human guanylate-binding protein family.J. Interf. Cytokine Res. 2007; 27: 44-52Crossref PubMed Scopus (0) Google Scholar). Differences in pathogen-targeting have been noted depending on the pathogen and cell type. We previously showed that human GBP1 fails to target the apicomplexan parasite Toxoplasma gondii (Tg) and two intracellular bacterial pathogens, Chlamydia trachomatis and Salmonella enterica subsp. enterica serovar Typhimurium (STm), in human A549 epithelial cells; however, GBP1 is required for the restriction of parasite growth, but not the bacterial pathogens (Johnston et al., 2016Johnston A.C. Piro A. Clough B. Siew M. Virreira Winter S. Coers J. Frickel E.-M. Human GBP1 does not localize to pathogen vacuoles but restricts Toxoplasma gondii.Cell. Microbiol. 2016; 18: 1056-1064Crossref PubMed Scopus (42) Google Scholar). On the other hand, in human macrophages GBP1 localizes to Tg, Chlamydia, and STm, but whether it can disrupt membranes that enclose these pathogens is not known (Al-Zeer et al., 2013Al-Zeer M.A. Al-Younes H.M. Lauster D. Abu Lubad M. Meyer T.F. Autophagy restricts Chlamydia trachomatis growth in human macrophages via IFNG-inducible guanylate binding proteins.Autophagy. 2013; 9: 50-62Crossref PubMed Scopus (66) Google Scholar; Fisch et al., 2019aFisch D. Bando H. Clough B. Hornung V. Yamamoto M. Shenoy A.R. Frickel E.M. Human GBP1 is a microbe-specific gatekeeper of macrophage apoptosis and pyroptosis.EMBO J. 2019; 38: e100926Crossref PubMed Scopus (32) Google Scholar). During Tg or STm infection-induced death of human macrophages, GBP1 targeting to pathogens is necessary, even though downstream mechanisms of cell death are distinct. Since Tg induces the loss of several inflammasome proteins, including NLRP3 (NOD, leucine rich repeat and pyrin domain containing protein 3) and caspase-1, human macrophages undergo atypical apoptosis through the assembly of AIM2 (absent in melanoma 2) -ASC (apoptotic-associated speck-like protein with a CARD)-caspase-8 complexes. In contrast, GBP1 promotes activation of caspase-4 following its recruitment to STm, resulting in enhanced pyroptosis (Fisch et al., 2019aFisch D. Bando H. Clough B. Hornung V. Yamamoto M. Shenoy A.R. Frickel E.M. Human GBP1 is a microbe-specific gatekeeper of macrophage apoptosis and pyroptosis.EMBO J. 2019; 38: e100926Crossref PubMed Scopus (32) Google Scholar). Although our previous work suggested that GBP1 is involved in PAMP release for detection by these PRRs during natural infection, the underlying mechanisms involved in liberating microbial ligands was not investigated (Fisch et al., 2019aFisch D. Bando H. Clough B. Hornung V. Yamamoto M. Shenoy A.R. Frickel E.M. Human GBP1 is a microbe-specific gatekeeper of macrophage apoptosis and pyroptosis.EMBO J. 2019; 38: e100926Crossref PubMed Scopus (32) Google Scholar). In this study we show that GBP1 contributes to the lysis of parasite-containing vacuoles and the plasma membrane of Tg by employing two assays. We also show that GBP1 exclusively targets STm that are already cytosolic and does not contribute to their ability to reach the cytosol of human macrophages. In contrast, during STm infection, caspase-1 cleaves and inactivates GBP1, and thereby reduces its ability to recruit caspase-4. These studies reveal the feedback inhibition of GBP1-caspase-4-driven pyroptosis during STm infection and its dual membrane-disruptive actions during Tg infection. As GBP1 elicits divergent host cell death programs in response to Tg and STm, we sought to investigate the upstream mechanisms of GBP1 during infection by these two unrelated pathogens. We previously correlated GBP1 recruitment to Tg parasitophorous vacuoles (PVs) to the activation of AIM2-caspase-8 and recognition of parasite DNA (Fisch et al., 2019aFisch D. Bando H. Clough B. Hornung V. Yamamoto M. Shenoy A.R. Frickel E.M. Human GBP1 is a microbe-specific gatekeeper of macrophage apoptosis and pyroptosis.EMBO J. 2019; 38: e100926Crossref PubMed Scopus (32) Google Scholar). We hypothesized that, like some murine Gbps (Degrandi et al., 2013Degrandi D. Kravets E. Konermann C. Beuter-Gunia C. Klümpers V. Lahme S. Wischmann E. Mausberg A.K. Beer-Hammer S. Pfeffer K. Murine guanylate binding protein 2 (mGBP2) controls Toxoplasma gondii replication.Proc. Natl. Acad. Sci. USA. 2013; 110: 294-299Crossref PubMed Scopus (102) Google Scholar; Kravets et al., 2016Kravets E. Degrandi D. Ma Q. Peulen T.-O.O. Klümpers V. Felekyan S. Kühnemuth R. Weidtkamp-Peters S. Seidel C.A. Pfeffer K. Guanylate binding proteins directly attack Toxoplasma gondii via supramolecular complexes.eLife. 2016; 5: e11479Crossref PubMed Google Scholar; Selleck et al., 2013Selleck E.M. Fentress S.J. Beatty W.L. Degrandi D. Pfeffer K. Virgin 4th, H.W. Macmicking J.D. Sibley L.D. Guanylate-binding protein 1 (Gbp1) contributes to cell-autonomous immunity against Toxoplasma gondii.PLoS Pathog. 2013; 9: e1003320Crossref PubMed Scopus (104) Google Scholar; Yamamoto et al., 2012Yamamoto M. Okuyama M. Ma J.S. Kimura T. Kamiyama N. Saiga H. Ohshima J. Sasai M. Kayama H. Okamoto T. et al.A cluster of interferon-γ-inducible p65 GTPases plays a critical role in host defense against Toxoplasma gondii.Immunity. 2012; 37: 302-313Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar), human GBP1 promotes PV opening and cytosolic access to intravacuolar pathogens. Extending our previous finding of GBP1 recruiting to the PV, we also localized GBP1 directly to the surface of Tg using AiryScan super-resolution microscopy (Figure 1A). To test whether GBP1 can disrupt Tg PVs, we used the cytosolic dye CellMask, which is excluded from PVs but enters once the PV membrane (PVM) is disrupted (Figure 1B). As positive control for this assay, PVs were chemically disrupted by detergent-mediated permeabilization, resulting in higher fluorescence within the vacuoles as compared to untreated cells (Figure 1B). Increased CellMask dye intensity within naturally disrupted PVs could be reliably quantified using our artificial inte" @default.
• W3048774419 created "2020-08-18" @default.
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• W3048774419 date "2020-08-01" @default.
• W3048774419 modified "2023-10-15" @default.
• W3048774419 title "Human GBP1 Differentially Targets Salmonella and Toxoplasma to License Recognition of Microbial Ligands and Caspase-Mediated Death" @default.
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