Abstract
Legionella species are Gram-negative ubiquitous environmental bacteria, which thrive in biofilms and parasitize protozoa. Employing an evolutionarily conserved mechanism, the opportunistic pathogens also replicate intracellularly in mammalian macrophages. This feature is a prerequisite for the pathogenicity of Legionella pneumophila, which causes the vast majority of clinical cases of a severe pneumonia, termed “Legionnaires’ disease.” In macrophages as well as in amoeba, L. pneumophila grows in a distinct membrane-bound compartment, the Legionella-containing vacuole (LCV). Formation of this replication-permissive pathogen compartment requires the bacterial Dot/Icm type IV secretion system (T4SS). Through the T4SS as many as 300 different “effector” proteins are injected into host cells, where they presumably subvert pivotal processes. Less than 40 Dot/Icm substrates have been characterized in detail to date, a number of which show unprecedented biological activities. Some of these effector proteins target host cell small GTPases, phosphoinositide lipids, the chelator phytate, the ubiquitination machinery, the retromer complex, the actin cytoskeleton, or the autophagy pathway. A recently discovered class of L. pneumophila effectors modulates the activity of other effectors and is termed “metaeffectors.” Here, we summarize recent insight into the cellular functions and biochemical activities of L. pneumophila effectors and metaeffectors targeting the host’s endocytic, retrograde, or autophagic pathways.
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References
Amer AO, Swanson MS (2005) Autophagy is an immediate macrophage response to Legionella pneumophila. Cell Microbiol 7:765–778. https://doi.org/10.1111/j.1462-5822.2005.00509.x
Arasaki K, Mikami Y, Shames SR, Inoue H, Wakana Y, Tagaya M (2017) Legionella effector Lpg1137 shuts down ER-mitochondria communication through cleavage of syntaxin 17. Nat Commun 8:15406. https://doi.org/10.1038/ncomms15406
Asrat S, de Jesus DA, Hempstead AD, Ramabhadran V, Isberg RR (2014) Bacterial pathogen manipulation of host membrane trafficking. Annu Rev Cell Dev Biol 30:79–109. https://doi.org/10.1146/annurev-cellbio-100913-013439
Banga S, Gao P, Shen X, Fiscus V, Zong WX, Chen L, Luo ZQ (2007) Legionella pneumophila inhibits macrophage apoptosis by targeting pro-death members of the Bcl2 protein family. Proc Natl Acad Sci USA 104:5121–5126
Bardill JP, Miller JL, Vogel JP (2005) IcmS-dependent translocation of SdeA into macrophages by the Legionella pneumophila type IV secretion system. Mol Microbiol 56:90–103
Bärlocher K, Hutter CAJ, Swart AL et al (2017) Structural insights into Legionella RidL-Vps29 retromer subunit interaction reveal displacement of the regulator TBC1D5. Nat Commun 8:1543. https://doi.org/10.1038/s41467-017-01512-5
Bhogaraju S, Kalayil S, Liu Y, Bonn F, Colby T, Matic I, Dikic I (2016) Phosphoribosylation of ubiquitin promotes serine ubiquitination and impairs conventional ubiquitination. Cell 167(1636–1649):e1613. https://doi.org/10.1016/j.cell.2016.11.019
Brombacher E, Urwyler S, Ragaz C, Weber SS, Kami K, Overduin M, Hilbi H (2009) Rab1 guanine nucleotide exchange factor SidM is a major phosphatidylinositol 4-phosphate-binding effector protein of Legionella pneumophila. J Biol Chem 284:4846–4856. M807505200 [pii]. https://doi.org/10.1074/jbc.M807505200
Bruckert WM, Abu Kwaik Y (2015) Complete and ubiquitinated proteome of the Legionella-containing vacuole within human macrophages. J Proteome Res 14:236–248. https://doi.org/10.1021/pr500765x
Chen Y, Machner MP (2013) Targeting of the small GTPase Rab6A’ by the Legionella pneumophila effector LidA. Infect Immun 81:2226–2235. https://doi.org/10.1128/IAI.00157-13
Chen J, de Felipe KS, Clarke M, Lu H, Anderson OR, Segal G, Shuman HA (2004) Legionella effectors that promote nonlytic release from protozoa. Science 303:1358–1361
Cheng W, Yin K, Lu D et al (2012) Structural insights into a unique Legionella pneumophila effector LidA recognizing both GDP and GTP bound Rab1 in their active state. PLoS Pathog 8:e1002528. https://doi.org/10.1371/journal.ppat.1002528
Choy A, Dancourt J, Mugo B, O’Connor TJ, Isberg RR, Melia TJ, Roy CR (2012) The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 338:1072–1076. https://doi.org/10.1126/science.1227026
Conover GM, Derre I, Vogel JP, Isberg RR (2003) The Legionella pneumophila LidA protein: a translocated substrate of the Dot/Icm system associated with maintenance of bacterial integrity. Mol Microbiol 48:305–321
de Felipe KS, Pampou S, Jovanovic OS, Pericone CD, Ye SF, Kalachikov S, Shuman HA (2005) Evidence for acquisition of Legionella type IV secretion substrates via interdomain horizontal gene transfer. J Bacteriol 187:7716–7726
Del Campo CM, Mishra AK, Wang YH, Roy CR, Janmey PA, Lambright DG (2014) Structural basis for PI(4)P-specific membrane recruitment of the Legionella pneumophila effector DrrA/SidM. Structure 22:397–408. https://doi.org/10.1016/j.str.2013.12.018
Derre I, Isberg RR (2005) LidA, a translocated substrate of the Legionella pneumophila type IV secretion system, interferes with the early secretory pathway. Infect Immun 73:4370–4380
Di Paolo G, De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–657
Dolinsky S, Haneburger I, Cichy A, Hannemann M, Itzen A, Hilbi H (2014) The Legionella longbeachae Dot/Icm substrate SidC selectively binds phosphatidylinositol 4-phosphate with nanomolar affinity and promotes pathogen vacuole-endoplasmic reticulum interactions. Infect Immun 82:4021–4033. https://doi.org/10.1128/IAI.01685-14
Dong N, Niu M, Hu L, Yao Q, Zhou R, Shao F (2016) Modulation of membrane phosphoinositide dynamics by the phosphatidylinositide 4-kinase activity of the Legionella LepB effector. Nat Microbiol 2:16236. https://doi.org/10.1038/nmicrobiol.2016.236
Dorer MS, Kirton D, Bader JS, Isberg RR (2006) RNA interference analysis of Legionella in Drosophila cells: exploitation of early secretory apparatus dynamics. PLoS Pathog 2:e34
Escoll P, Song OR, Viana F et al (2017) Legionella pneumophila modulates mitochondrial dynamics to trigger metabolic repurposing of infected macrophages. Cell Host Microbe 22(302–316):e307. https://doi.org/10.1016/j.chom.2017.07.020
Finsel I, Hilbi H (2015) Formation of a pathogen vacuole according to Legionella pneumophila: how to kill one bird with many stones. Cell Microbiol 17:935–950. https://doi.org/10.1111/cmi.12450
Finsel I, Ragaz C, Hoffmann C et al (2013) The Legionella effector RidL inhibits retrograde trafficking to promote intracellular replication. Cell Host Microbe 14:38–50. https://doi.org/10.1016/j.chom.2013.06.001
Franco IS, Shohdy N, Shuman HA (2012) The Legionella pneumophila effector VipA is an actin nucleator that alters host cell organelle trafficking. PLoS Pathog 8:e1002546. https://doi.org/10.1371/journal.ppat.1002546
Gaspar AH, Machner MP (2014) VipD is a Rab5-activated phospholipase A1 that protects Legionella pneumophila from endosomal fusion. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1316376111
Gazdag EM, Streller A, Haneburger I, Hilbi H, Vetter IR, Goody RS, Itzen A (2013) Mechanism of Rab1b deactivation by the Legionella pneumophila GAP LepB. EMBO Rep 14:199–205. https://doi.org/10.1038/embor.2012.211
Gazdag EM, Schobel S, Shkumatov AV, Goody RS, Itzen A (2014) The structure of the N-terminal domain of the Legionella protein SidC. J Struct Biol 186. https://doi.org/10.1016/j.jsb.2014.02.003
Gomez-Valero L, Rusniok C, Cazalet C, Buchrieser C (2011) Comparative and functional genomics of Legionella identified eukaryotic like proteins as key players in host-pathogen interactions. Front Microbiol 2:208. https://doi.org/10.3389/fmicb.2011.00208
Grohmann E, Christie PJ, Waksman G, Backert S (2018) Type IV secretion in Gram-negative and Gram-positive bacteria. Mol Microbiol 107:455–471. https://doi.org/10.1111/mmi.13896
Guo Z, Stephenson R, Qiu J, Zheng S, Luo ZQ (2014) A Legionella effector modulates host cytoskeletal structure by inhibiting actin polymerization. Microbes Infect 16:225–236. https://doi.org/10.1016/j.micinf.2013.11.007
Guttler T, Görlich D (2011) Ran-dependent nuclear export mediators: a structural perspective. EMBO J 30:3457–3474. https://doi.org/10.1038/emboj.2011.287
Hamasaki M, Furuta N, Matsuda A et al (2013) Autophagosomes form at ER-mitochondria contact sites. Nature 495:389–393. https://doi.org/10.1038/nature11910
Hammond GR, Machner MP, Balla T (2014) A novel probe for phosphatidylinositol 4-phosphate reveals multiple pools beyond the Golgi. J Cell Biol 205:113–126. https://doi.org/10.1083/jcb.201312072
Haneburger I, Hilbi H (2013) Phosphoinositide lipids and the Legionella pathogen vacuole. Curr Top Microbiol Immunol 376:155–173. https://doi.org/10.1007/82_2013_341
Hardiman CA, Roy CR (2014) AMPylation is critical for Rab1 localization to vacuoles containing Legionella pneumophila. MBio 5:e01035–01013. https://doi.org/10.1128/mBio.01035-13
Harding CR, Mattheis C, Mousnier A, Oates CV, Hartland EL, Frankel G, Schroeder GN (2013) LtpD is a novel Legionella pneumophila effector that binds phosphatidylinositol 3-phosphate and inositol monophosphatase IMPA1. Infect Immun 81:4261–4270. https://doi.org/10.1128/IAI.01054-13
Heidtman M, Chen EJ, Moy MY, Isberg RR (2009) Large-scale identification of Legionella pneumophila Dot/Icm substrates that modulate host cell vesicle trafficking pathways. Cell Microbiol 11:230–248. https://doi.org/10.1111/j.1462-5822.2008.01249.x
Herweg JA, Hansmeier N, Otto A et al (2015) Purification and proteomics of pathogen-modified vacuoles and membranes. Front Cell Infect Microbiol 5:48. https://doi.org/10.3389/fcimb.2015.00048
Hilbi H, Haas A (2012) Secretive bacterial pathogens and the secretory pathway. Traffic 13:1187–1197. https://doi.org/10.1111/j.1600-0854.2012.01344.x
Hilbi H, Kortholt A (2017) Role of the small GTPase Rap1 in signal transduction, cell dynamics and bacterial infection. Small GTPases 20:1–7. https://doi.org/10.1080/21541248.2017.1331721
Hilbi H, Hoffmann C, Harrison CF (2011a) Legionella spp. outdoors: colonization, communication and persistence. Environ Microbiol Rep 3:286–296
Hilbi H, Weber S, Finsel I (2011b) Anchors for effectors: subversion of phosphoinositide lipids by Legionella. Front Microbiol 2:91. https://doi.org/10.3389/fmicb.2011.00091
Hilbi H, Rothmeier E, Hoffmann C, Harrison CF (2014) Beyond Rab GTPases Legionella activates the small GTPase Ran to promote microtubule polymerization, pathogen vacuole motility, and infection. Small GTPases 5:1–6
Hochstrasser R, Hilbi H (2017) Intra-species and inter-kingdom signaling of Legionella pneumophila. Front Microbiol 8:79. https://doi.org/10.3389/fmicb.2017.00079
Hoffmann C, Finsel I, Hilbi H (2013) Pathogen vacuole purification from Legionella-infected amoeba and macrophages. Methods Mol Biol 954:309–321. https://doi.org/10.1007/978-1-62703-161-5_18
Hoffmann C, Finsel I, Otto A et al (2014a) Functional analysis of novel Rab GTPases identified in the proteome of purified Legionella-containing vacuoles from macrophages. Cell Microbiol 16:1034–1052. https://doi.org/10.1111/cmi.12256
Hoffmann C, Harrison CF, Hilbi H (2014b) The natural alternative: protozoa as cellular models for Legionella infection. Cell Microbiol 16:15–26. https://doi.org/10.1111/cmi.12235
Horenkamp FA, Mukherjee S, Alix E, Schauder CM, Hubber AM, Roy CR, Reinisch KM (2014) Legionella pneumophila subversion of host vesicular transport by SidC effector proteins. Traffic 15:488–499. https://doi.org/10.1111/tra.12158
Horenkamp FA, Kauffman KJ, Kohler LJ et al (2015) The Legionella anti-autophagy effector RavZ targets the autophagosome via PI3P- and curvature-sensing motifs. Dev Cell 34:569–576. https://doi.org/10.1016/j.devcel.2015.08.010
Horwitz MA (1983) Formation of a novel phagosome by the Legionnaires’ disease bacterium (Legionella pneumophila) in human monocytes. J Exp Med 158:1319–1331
Hsu F, Zhu W, Brennan L, Tao L, Luo ZQ, Mao Y (2012) Structural basis for substrate recognition by a unique Legionella phosphoinositide phosphatase. Proc Natl Acad Sci U S A 109:13567–13572. https://doi.org/10.1073/pnas.1207903109
Hsu F, Luo X, Qiu J et al (2014) The Legionella effector SidC defines a unique family of ubiquitin ligases important for bacterial phagosomal remodeling. Proc Natl Acad Sci USA 111:10538–10543. https://doi.org/10.1073/pnas.1402605111
Hubber A, Roy CR (2010) Modulation of host cell function by Legionella pneumophila type IV effectors. Annu Rev Cell Dev Biol 26:261–283. https://doi.org/10.1146/annurev-cellbio-100109-104034
Hubber A, Arasaki K, Nakatsu F et al (2014) The machinery at endoplasmic reticulum-plasma membrane contact sites contributes to spatial regulation of multiple Legionella effector proteins. PLoS Pathog 10:e1004222. https://doi.org/10.1371/journal.ppat.1004222
Ingmundson A, Delprato A, Lambright DG, Roy CR (2007) Legionella pneumophila proteins that regulate Rab1 membrane cycling. Nature 450:365–369. https://doi.org/10.1038/nature06336
Isberg RR, O’Connor TJ, Heidtman M (2009) The Legionella pneumophila replication vacuole: making a cosy niche inside host cells. Nat Rev Microbiol 7:13–24. https://doi.org/10.1038/nrmicro1967
Itakura E, Kishi-Itakura C, Mizushima N (2012) The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151:1256–1269. https://doi.org/10.1016/j.cell.2012.11.001
Itzen A, Goody RS (2011) Covalent coercion by Legionella pneumophila. Cell Host Microbe 10:89–91. https://doi.org/10.1016/j.chom.2011.08.002
Ivanov SS, Roy CR (2009) Modulation of ubiquitin dynamics and suppression of DALIS formation by the Legionella pneumophila Dot/Icm system. Cell Microbiol 11:261–278. https://doi.org/10.1111/j.1462-5822.2008.01251.x
Jank T, Bohmer KE, Tzivelekidis T, Schwan C, Belyi Y, Aktories K (2012) Domain organization of Legionella effector SetA. Cell Microbiol 14:852–868. https://doi.org/10.1111/j.1462-5822.2012.01761.x
Jeong KC, Sexton JA, Vogel JP (2015) Spatiotemporal regulation of a Legionella pneumophila T4SS substrate by the metaeffector SidJ. PLoS Pathog 11:e1004695. https://doi.org/10.1371/journal.ppat.1004695
Jeschke A, Zehethofer N, Lindner B et al (2015) Phosphatidylinositol 4-phosphate and phosphatidylinositol 3-phosphate regulate phagolysosome biogenesis. Proc Natl Acad Sci USA 112:4636–4641. https://doi.org/10.1073/pnas.1423456112
Johannes L, Popoff V (2008) Tracing the retrograde route in protein trafficking. Cell 135:1175–1187. https://doi.org/10.1016/j.cell.2008.12.009
Kotewicz KM, Ramabhadran V, Sjoblom N et al (2017) A single Legionella effector catalyzes a multistep ubiquitination pathway to rearrange tubular endoplasmic reticulum for replication. Cell Host Microbe 21:169–181. https://doi.org/10.1016/j.chom.2016.12.007
Ku B, Lee KH, Park WS et al (2012) VipD of Legionella pneumophila targets activated Rab5 and Rab22 to interfere with endosomal trafficking in macrophages. PLoS Pathog 8:e1003082. https://doi.org/10.1371/journal.ppat.1003082
Kubori T, Nagai H (2016) The Type IVB secretion system: an enigmatic chimera. Curr Opin Microbiol 29:22–29. https://doi.org/10.1016/j.mib.2015.10.001
Kubori T, Hyakutake A, Nagai H (2008) Legionella translocates an E3 ubiquitin ligase that has multiple U-boxes with distinct functions. Mol Microbiol 67:1307–1319. https://doi.org/10.1111/j.1365-2958.2008.06124.x
Kubori T, Shinzawa N, Kanuka H, Nagai H (2010) Legionella metaeffector exploits host proteasome to temporally regulate cognate effector. PLoS Pathog 6:e1001216. https://doi.org/10.1371/journal.ppat.1001216
Kwon DH, Kim L, Kim BW, Kim JH, Roh KH, Choi EJ, Song HK (2017a) A novel conformation of the LC3-interacting region motif revealed by the structure of a complex between LC3B and RavZ. Biochem Biophys Res Commun 490:1093–1099. https://doi.org/10.1016/j.bbrc.2017.06.173
Kwon DH, Kim S, Jung YO et al (2017b) The 1:2 complex between RavZ and LC3 reveals a mechanism for deconjugation of LC3 on the phagophore membrane. Autophagy 13:70–81. https://doi.org/10.1080/15548627.2016.1243199
Laguna RK, Creasey EA, Li Z, Valtz N, Isberg RR (2006) A Legionella pneumophila-translocated substrate that is required for growth within macrophages and protection from host cell death. Proc Natl Acad Sci USA 103:18745–18750
Levine B, Mizushima N, Virgin HW (2011) Autophagy in immunity and inflammation. Nature 469:323–335. https://doi.org/10.1038/nature09782
Liu Y, Luo ZQ (2007) The Legionella pneumophila effector SidJ is required for efficient recruitment of endoplasmic reticulum proteins to the bacterial phagosome. Infect Immun 75:592–603
Lu H, Clarke M (2005) Dynamic properties of Legionella-containing phagosomes in Dictyostelium amoebae. Cell Microbiol 7:995–1007
Lucas M, Gaspar AH, Pallara C, Rojas AL, Fernandez-Recio J, Machner MP, Hierro A (2014) Structural basis for the recruitment and activation of the Legionella phospholipase VipD by the host GTPase Rab5. Proc Natl Acad Sci USA 111:E3514–3523. https://doi.org/10.1073/pnas.1405391111
Luo ZQ, Isberg RR (2004) Multiple substrates of the Legionella pneumophila Dot/Icm system identified by interbacterial protein transfer. Proc Natl Acad Sci USA 101:841–846
Machner MP, Isberg RR (2006) Targeting of host Rab GTPase function by the intravacuolar pathogen Legionella pneumophila. Dev Cell 11:47–56
Machner MP, Isberg RR (2007) A bifunctional bacterial protein links GDI displacement to Rab1 activation. Science 318:974–977. https://doi.org/10.1126/science.1149121
Manske C, Hilbi H (2014) Metabolism of the vacuolar pathogen Legionella and implications for virulence. Front Cell Infect Microbiol 4:125. https://doi.org/10.3389/fcimb.2014.00125
Mehta ZB, Pietka G, Lowe M (2014) The cellular and physiological functions of the Lowe syndrome protein OCRL1. Traffic 15:471–487. https://doi.org/10.1111/tra.12160
Michard C, Sperandio D, Bailo N et al (2015) The Legionella kinase LegK2 targets the ARP2/3 complex to inhibit actin nucleation on phagosomes and allow bacterial evasion of the late endocytic pathway. MBio 6:e00354-15. https://doi.org/10.1128/mBio.00354-15
Mishra AK, Del Campo CM, Collins RE, Roy CR, Lambright DG (2013) The Legionella pneumophila GTPase activating protein LepB accelerates Rab1 deactivation by a non-canonical hydrolytic mechanism. J Biol Chem 288:24000–24011. https://doi.org/10.1074/jbc.M113.470625
Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147:728–741. https://doi.org/10.1016/j.cell.2011.10.026
Molmeret M, Horn M, Wagner M, Santic M, Abu Kwaik Y (2005) Amoebae as training grounds for intracellular bacterial pathogens. Appl Environ Microbiol 71:20–28
Molofsky AB, Swanson MS (2004) Differentiate to thrive: lessons from the Legionella pneumophila life cycle. Mol Microbiol 53:29–40
Mukherjee S, Liu X, Arasaki K, McDonough J, Galan JE, Roy CR (2011) Modulation of Rab GTPase function by a protein phosphocholine transferase. Nature 477:103–106. https://doi.org/10.1038/nature10335
Müller MP, Peters H, Blumer J, Blankenfeldt W, Goody RS, Itzen A (2010) The Legionella effector protein DrrA AMPylates the membrane traffic regulator Rab1b. Science 329:946–949. https://doi.org/10.1126/science.1192276
Murata T, Delprato A, Ingmundson A, Toomre DK, Lambright DG, Roy CR (2006) The Legionella pneumophila effector protein DrrA is a Rab1 guanine nucleotide-exchange factor. Nat Cell Biol 8:971–977
Naujoks J, Tabeling C, Dill BD et al (2016) IFNs modify the proteome of Legionella-containing vacuoles and restrict infection via IRG1-derived itaconic acid. PLoS Pathog 12:e1005408. https://doi.org/10.1371/journal.ppat.1005408
Neunuebel MR, Mohammadi S, Jarnik M, Machner MP (2012) Legionella pneumophila LidA affects nucleotide binding and activity of the host GTPase Rab1. J Bacteriol 194:1389–1400. https://doi.org/10.1128/JB.06306-11
Newton HJ, Ang DK, van Driel IR, Hartland EL (2010) Molecular pathogenesis of infections caused by Legionella pneumophila. Clin Microbiol Rev 23:274–298. https://doi.org/10.1128/CMR.00052-09
O’Connor TJ, Adepoju Y, Boyd D, Isberg RR (2011) Minimization of the Legionella pneumophila genome reveals chromosomal regions involved in host range expansion. Proc Natl Acad Sci USA 108:14733–14740. https://doi.org/10.1073/pnas.1111678108
Oesterlin LK, Goody RS, Itzen A (2012) Posttranslational modifications of Rab proteins cause effective displacement of GDP dissociation inhibitor. Proc Natl Acad Sci USA 109:5621–5626. https://doi.org/10.1073/pnas.1121161109
Otto GP, Wu MY, Clarke M et al (2004) Macroautophagy is dispensable for intracellular replication of Legionella pneumophila in Dictyostelium discoideum. Mol Microbiol 51:63–72
Personnic N, Bärlocher K, Finsel I, Hilbi H (2016) Subversion of retrograde trafficking by translocated pathogen effectors. Trends Microbiol 24:450–462. https://doi.org/10.1016/j.tim.2016.02.003
Qiu J, Luo ZQ (2017) Legionella and Coxiella effectors: strength in diversity and activity. Nat Rev Microbiol. https://doi.org/10.1038/nrmicro.2017.67
Qiu J, Sheedlo MJ, Yu K et al (2016) Ubiquitination independent of E1 and E2 enzymes by bacterial effectors. Nature 533:120–124. https://doi.org/10.1038/nature17657
Qiu J, Yu K, Fei X et al (2017) A unique deubiquitinase that deconjugates phosphoribosyl-linked protein ubiquitination. Cell Res. https://doi.org/10.1038/cr.2017.66
Quaile AT, Urbanus ML, Stogios PJ, Nocek B, Skarina T, Ensminger AW, Savchenko A (2015) Molecular characterization of LubX: functional divergence of the U-Box fold by Legionella pneumophila. Structure 23:1459–1469. https://doi.org/10.1016/j.str.2015.05.020
Ragaz C, Pietsch H, Urwyler S, Tiaden A, Weber SS, Hilbi H (2008) The Legionella pneumophila phosphatidylinositol-4 phosphate-binding type IV substrate SidC recruits endoplasmic reticulum vesicles to a replication-permissive vacuole. Cell Microbiol 10:2416–2433. https://doi.org/10.1111/j.1462-5822.2008.01219.x
Randow F, Youle RJ (2014) Self and nonself: how autophagy targets mitochondria and bacteria. Cell Host Microbe 15:403–411. https://doi.org/10.1016/j.chom.2014.03.012
Robinson CG, Roy CR (2006) Attachment and fusion of endoplasmic reticulum with vacuoles containing Legionella pneumophila. Cell Microbiol 8:793–805
Rolando M, Escoll P, Nora T et al (2016) Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy. Proc Natl Acad Sci USA 113:1901–1906. https://doi.org/10.1073/pnas.1522067113
Rothmeier E, Pfaffinger G, Hoffmann C et al (2013) Activation of Ran GTPase by a Legionella effector promotes microtubule polymerization, pathogen vacuole motility and infection. PLoS Pathog 9:e1003598. https://doi.org/10.1371/journal.ppat.1003598
Schmölders J, Manske C, Otto A et al (2017) Comparative proteomics of purified pathogen vacuoles correlates intracellular replication of Legionella pneumophila with the small GTPase Ras-related protein 1 (Rap1). Mol Cell Proteomics 16:622–641. https://doi.org/10.1074/mcp.M116.063453
Schoebel S, Oesterlin LK, Blankenfeldt W, Goody RS, Itzen A (2009) RabGDI displacement by DrrA from Legionella is a consequence of its guanine nucleotide exchange activity. Mol Cell 36:1060–1072. https://doi.org/10.1016/j.molcel.2009.11.014
Schoebel S, Blankenfeldt W, Goody RS, Itzen A (2010) High-affinity binding of phosphatidylinositol 4-phosphate by Legionella pneumophila DrrA. EMBO Rep 11:598–604. https://doi.org/10.1038/embor.2010.97
Schoebel S, Cichy AL, Goody RS, Itzen A (2011) Protein LidA from Legionella is a Rab GTPase supereffector. Proc Natl Acad Sci USA 108:17945–17950. https://doi.org/10.1073/pnas.1113133108
Seaman MN (2012) The retromer complex - endosomal protein recycling and beyond. J Cell Sci 125:4693–4702. https://doi.org/10.1242/jcs.103440
Sheedlo MJ, Qiu J, Tan Y, Paul LN, Luo ZQ, Das C (2015) Structural basis of substrate recognition by a bacterial deubiquitinase important for dynamics of phagosome ubiquitination. Proc Natl Acad Sci USA 112:15090–15095. https://doi.org/10.1073/pnas.1514568112
Sherwood RK, Roy CR (2013) A Rab-centric perspective of bacterial pathogen-occupied vacuoles. Cell Host Microbe 14:256–268. https://doi.org/10.1016/j.chom.2013.08.010
Shevchuk O, Batzilla C, Hägele S et al (2009) Proteomic analysis of Legionella-containing phagosomes isolated from Dictyostelium. Int J Med Microbiol 299:489–508. https://doi.org/10.1016/j.ijmm.2009.03.006
Shohdy N, Efe JA, Emr SD, Shuman HA (2005) Pathogen effector protein screening in yeast identifies Legionella factors that interfere with membrane trafficking. Proc Natl Acad Sci USA 102:4866–4871
Simon S, Wagner MA, Rothmeier E, Müller-Taubenberger A, Hilbi H (2014) Dot/Icm-dependent inhibition of phagocyte migration by Legionella is antagonized by a translocated Ran GTPase activator. Cell Microbiol 16:977–992. https://doi.org/10.1111/cmi.12258
Steiner B, Swart AL, Welin A et al (2017) ER remodeling by the large GTPase atlastin promotes vacuolar growth of Legionella pneumophila. EMBO Rep 18:1817–1836. https://doi.org/10.15252/embr.201743903
Suh HY, Lee DW, Lee KH et al (2010) Structural insights into the dual nucleotide exchange and GDI displacement activity of SidM/DrrA. EMBO J 29:496–504. https://doi.org/10.1038/emboj.2009.347
Swanson MS, Isberg RR (1995) Association of Legionella pneumophila with the macrophage endoplasmic reticulum. Infect Immun 63:3609–3620
Tan Y, Luo ZQ (2011) Legionella pneumophila SidD is a deAMPylase that modifies Rab1. Nature 475:506–509. https://doi.org/10.1038/nature10307
Tan Y, Arnold RJ, Luo ZQ (2011) Legionella pneumophila regulates the small GTPase Rab1 activity by reversible phosphorylcholination. Proc Natl Acad Sci U S A 108:21212–21217. https://doi.org/10.1073/pnas.1114023109
Toulabi L, Wu X, Cheng Y, Mao Y (2013) Identification and structural characterization of a Legionella phosphoinositide phosphatase. J Biol Chem 288:24518–24527. https://doi.org/10.1074/jbc.M113.474239
Urbanus ML, Quaile AT, Stogios PJ et al (2016) Diverse mechanisms of metaeffector activity in an intracellular bacterial pathogen Legionella pneumophila. Mol Syst Biol 12:893. https://doi.org/10.15252/msb.20167381
Urwyler S, Brombacher E, Hilbi H (2009a) Endosomal and secretory markers of the Legionella-containing vacuole. Commun Integr Biol 2:107–109
Urwyler S, Nyfeler Y, Ragaz C, Lee H, Mueller LN, Aebersold R, Hilbi H (2009b) Proteome analysis of Legionella vacuoles purified by magnetic immunoseparation reveals secretory and endosomal GTPases. Traffic 10:76–87. https://doi.org/10.1111/j.1600-0854.2008.00851.x
Urwyler S, Finsel I, Ragaz C, Hilbi H (2010) Isolation of Legionella-containing vacuoles by immuno-magnetic separation. In: Current protocols in cell biology. Unit 3, 34. https://doi.org/10.1002/0471143030.cb0334s46
VanRheenen SM, Luo ZQ, O’Connor T, Isberg RR (2006) Members of a Legionella pneumophila family of proteins with ExoU (phospholipase A) active sites are translocated to target cells. Infect Immun 74:3597–3606
Wandinger-Ness A, Zerial M (2014) Rab proteins and the compartmentalization of the endosomal system. Cold Spring Harb Perspect Biol 6:a022616. https://doi.org/10.1101/cshperspect.a022616
Weber SS, Ragaz C, Reus K, Nyfeler Y, Hilbi H (2006) Legionella pneumophila exploits PI(4)P to anchor secreted effector proteins to the replicative vacuole. PLoS Pathog 2:e46
Weber SS, Ragaz C, Hilbi H (2009a) The inositol polyphosphate 5-phosphatase OCRL1 restricts intracellular growth of Legionella, localizes to the replicative vacuole and binds to the bacterial effector LpnE. Cell Microbiol 11:442–460. https://doi.org/10.1111/j.1462-5822.2008.01266.x
Weber SS, Ragaz C, Hilbi H (2009b) Pathogen trafficking pathways and host phosphoinositide metabolism. Mol Microbiol 71:1341–1352. https://doi.org/10.1111/j.1365-2958.2009.06608.x
Weber S, Stirnimann CU, Wieser M et al (2014a) A type IV translocated Legionella cysteine phytase counteracts intracellular growth restriction by phytate. J Biol Chem 289:34175–34188. https://doi.org/10.1074/jbc.M114.592568
Weber S, Wagner M, Hilbi H (2014b) Live-cell imaging of phosphoinositide dynamics and membrane architecture during Legionella infection. MBio 5:e00839-00813. https://doi.org/10.1128/mBio.00839-13
Xu L, Shen X, Bryan A, Banga S, Swanson MS, Luo ZQ (2010) Inhibition of host vacuolar H+-ATPase activity by a Legionella pneumophila effector. PLoS Pathog 6:e1000822. https://doi.org/10.1371/journal.ppat.1000822
Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12:814–822. https://doi.org/10.1038/ncb0910-814
Yang A, Pantoom S, Wu YW (2017) Elucidation of the anti-autophagy mechanism of the Legionella effector RavZ using semisynthetic LC3 proteins. Elife 6. https://doi.org/10.7554/elife.23905
Zhen Y, Stenmark H (2015) Cellular functions of Rab GTPases at a glance. J Cell Sci 128:3171–3176. https://doi.org/10.1242/jcs.166074
Zhu Y, Hu L, Zhou Y, Yao Q, Liu L, Shao F (2010) Structural mechanism of host Rab1 activation by the bifunctional Legionella type IV effector SidM/DrrA. Proc Natl Acad Sci USA 107:4699–4704. https://doi.org/10.1073/pnas.0914231107
Zhu W, Hammad LA, Hsu F, Mao Y, Luo ZQ (2013) Induction of caspase 3 activation by multiple Legionella pneumophila Dot/Icm substrates. Cell Microbiol:1783–1795. https://doi.org/10.1111/cmi.12157
Zusman T, Aloni G, Halperin E, Kotzer H, Degtyar E, Feldman M, Segal G (2007) The response regulator PmrA is a major regulator of the Dot/Icm type IV secretion system in Legionella pneumophila and Coxiella burnetii. Mol Microbiol 63:1508–1523
Acknowledgements
Research in the laboratory of H. H. was supported by the Swiss National Science Foundation (SNF; 31003A_153200), the German Ministry of Education and Research (BMBF) in the context of the EU Infect-ERA initiative (project EUGENPATH), the Novartis Foundation for Medical-Biological Research, and the OPO foundation. Research in the laboratory of H. N. was supported in part by MEXT/JSPS KAKENHI Grants 15H01322, 15H04728, 16H05189, and 16K14724. Research in the laboratory of C. R. R. was funded by NIH grant R37 AI041699.
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Hilbi, H., Nagai, H., Kubori, T., Roy, C.R. (2017). Subversion of Host Membrane Dynamics by the Legionella Dot/Icm Type IV Secretion System. In: Backert, S., Grohmann, E. (eds) Type IV Secretion in Gram-Negative and Gram-Positive Bacteria. Current Topics in Microbiology and Immunology, vol 413. Springer, Cham. https://doi.org/10.1007/978-3-319-75241-9_9
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