Abstract
Intracellular bacterial pathogens have evolved sophisticated mechanisms to hijack host cellular processes to promote their survival and replication inside host cells. Over the past two decades, much attention has been given to the strategies employed by these pathogens to manipulate various vesicular trafficking pathways. But in the past 5 years, studies have brought to light that intracellular bacteria also target non-vesicular trafficking pathways. Here we review how three vacuolar pathogens, namely, Legionella, Chlamydia, and Coxiella hijack components of cellular MCS with or without the formation of stable MCS. A common theme in the manipulation of MCS by intracellular bacteria is the dependence on the secretion of bacterial effector proteins. During the early stages of the Legionella life cycle, the bacteria connects otherwise unrelated cellular pathways (i.e., components of ER-PM MCS, PI4KIIIα, and Sac1 and the early secretory pathway) to remodel its nascent vacuole into an ER-like compartment. Chlamydia and Coxiella vacuoles establish direct MCS with the ER and target lipid transfer proteins that contain a FFAT motif, CERT, and ORP1L, respectively, suggesting a common mechanism of VAP-dependent lipid acquisition. Chlamydia also recruits STIM1, an ER calcium sensor involved in store-operated calcium entry (SOCE) at ER-PM MCS, and elucidating the role of STIM1 at ER-Chlamydia inclusion MCS may uncover additional role for these contacts. Altogether, the manipulation of MCS by intracellular bacterial pathogens has open a new and exciting area of research to investigate the molecular mechanisms supporting pathogenesis.
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References
Agaisse H, Derré I (2014) Expression of the effector protein IncD in Chlamydia trachomatis mediates recruitment of the lipid transfer protein CERT and the endoplasmic reticulum-resident protein VAPB to the inclusion membrane. Infect Immun 82:2037–2047
Agaisse H, Derré I (2015) STIM1 is a novel component of ER-Chlamydia trachomatis inclusion membrane contact sites. PLoS One 10:e0125671
Arasaki K, Roy CR (2010) Legionella pneumophila promotes functional interactions between plasma membrane syntaxins and Sec22b. Traffic 11:587–600
Arasaki K, Toomre DK, Roy CR (2012) The Legionella pneumophila effector DrrA is sufficient to stimulate SNARE-dependent membrane fusion. Cell Host Microbe 11:46–57
Baird D, Stefan C, Audhya A, Weys S, Emr SD (2008) Assembly of the PtdIns 4-kinase Stt4 complex at the plasma membrane requires Ypp1 and Efr3. J Cell Biol 183:1061–1074
Balla A, Balla T (2006) Phosphatidylinositol 4-kinases: old enzymes with emerging functions. Trends Cell Biol 16:351–361
Balla A, Tuymetova G, Tsiomenko A, Varnai P, Balla T (2005) A plasma membrane pool of phosphatidylinositol 4-phosphate is generated by phosphatidylinositol 4-kinase type-III alpha: studies with the PH domains of the oxysterol binding protein and FAPP1. Mol Biol Cell 16:1282–1295
Barker JR, Koestler BJ, Carpenter VK, Burdette DL, Waters CM, Vance RE, Valdivia RH (2013) STING-dependent recognition of cyclic di-AMP mediates type I interferon responses during Chlamydia trachomatis infection. MBio 4:e00018–e00013
Beare PA (2012) Genetic manipulation of Coxiella burnetii. Adv Exp Med Biol 984:249–271
Beare PA, Heinzen RA (2014) Gene inactivation in Coxiella burnetii. Methods Mol Biol 1197:329–345
Beare PA, Gilk SD, Larson CL, Hill J, Stead CM, Omsland A, Cockrell DC, Howe D, Voth DE, Heinzen RA (2011) Dot/Icm type IVB secretion system requirements for Coxiella burnetii growth in human macrophages. MBio 2:e00175–e00111
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
Carabeo RA, Mead DJ, Hackstadt T (2003) Golgi-dependent transport of cholesterol to the Chlamydia trachomatis inclusion. Proc Natl Acad Sci USA 100:6771–6776
Carey KL, Newton HJ, Luhrmann A, Roy CR (2011) The Coxiella burnetii Dot/Icm system delivers a unique repertoire of type IV effectors into host cells and is required for intracellular replication. PLoS Pathog 7:e1002056
Dehoux P, Flores R, Dauga C, Zhong G, Subtil A (2011) Multi-genome identification and characterization of chlamydiae-specific type III secretion substrates: the Inc proteins. BMC Genomics 12:109
Delsing CE, Warris A, Bleeker-Rovers CP (2011) Q fever: still more queries than answers. Adv Exp Med Biol 719:133–143
Derré I, Swiss R, Agaisse H (2011) The lipid transfer protein CERT interacts with the Chlamydia inclusion protein IncD and participates to ER-Chlamydia inclusion membrane contact sites. PLoS Pathog 7:e1002092
Dumoux M, Clare DK, Saibil HR, Hayward RD (2012) Chlamydiae assemble a pathogen synapse to hijack the host endoplasmic reticulum. Traffic 13:1612–1627
Elwell CA, Jiang S, Kim JH, Lee A, Wittmann T, Hanada K, Melancon P, Engel JN (2011) Chlamydia trachomatis co-opts GBF1 and CERT to acquire host sphingomyelin for distinct roles during intracellular development. PLoS Pathog 7:e1002198
Elwell C, Mirrashidi K, Engel J (2016) Chlamydia cell biology and pathogenesis. Nat Rev Microbiol 14:385–400
Giordano F, Saheki Y, Idevall-Hagren O, Colombo SF, Pirruccello M, Milosevic I, Gracheva EO, Bagriantsev SN, Borgese N, De Camilli P (2013) PI(4,5)P(2)-dependent and Ca2+-regulated ER-PM interactions mediated by the extended synaptotagmins. Cell 153:1494–1509
Goody RS, Itzen A (2013) Modulation of small GTPases by Legionella. Curr Top Microbiol Immunol 376:117–133
Hackstadt T, Scidmore MA, Rockey DD (1995) Lipid metabolism in Chlamydia trachomatis-infected cells: directed trafficking of Golgi-derived sphingolipids to the chlamydial inclusion. Proc Natl Acad Sci USA 92:4877–4881
Hackstadt T, Rockey DD, Heinzen RA, Scidmore MA (1996) Chlamydia trachomatis interrupts an exocytic pathway to acquire endogenously synthesized sphingomyelin in transit from the Golgi apparatus to the plasma membrane. EMBO J 15:964–977
Hammond GR, Fischer MJ, Anderson KE, Holdich J, Koteci A, Balla T, Irvine RF (2012) PI4P and PI(4,5)P2 are essential but independent lipid determinants of membrane identity. Science 337:727–730
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
Hanada K, Kumagai K, Yasuda S, Miura Y, Kawano M, Fukasawa M, Nishijima M (2003) Molecular machinery for non-vesicular trafficking of ceramide. Nature 426:803–809
Hanada K, Kumagai K, Tomishige N, Yamaji T (2009) CERT-mediated trafficking of ceramide. Biochim Biophys Acta 1791:684–691
Hatch GM, McClarty G (1998) Phospholipid composition of purified Chlamydia trachomatis mimics that of the eucaryotic host cell. Infect Immun 66:3727–3735
Heinzen RA, Scidmore MA, Rockey DD, Hackstadt T (1996) Differential interaction with endocytic and exocytic pathways distinguish parasitophorous vacuoles of Coxiella burnetii and Chlamydia trachomatis. Infect Immun 64:796–809
Horwitz MA, Silverstein SC (1980) Legionnaires’ disease bacterium (Legionella pneumophila) multiples intracellularly in human monocytes. J Clin Invest 66:441–450
Howe D, Heinzen RA (2006) Coxiella burnetii inhabits a cholesterol-rich vacuole and influences cellular cholesterol metabolism. Cell Microbiol 8:496–507
Howe D, Melnicakova J, Barak I, Heinzen RA (2003) Maturation of the Coxiella burnetii parasitophorous vacuole requires bacterial protein synthesis but not replication. Cell Microbiol 5:469–480
Hubber A, Arasaki K, Nakatsu F, Hardiman C, Lambright D, De Camilli P, Nagai H, Roy CR (2014) The machinery at endoplasmic reticulum-plasma membrane contact sites contributes to spatial regulation of multiple Legionella effector proteins. PLoS Pathog 10:e1004222
Huitema K, van den Dikkenberg J, Brouwers JF, Holthuis JC (2004) Identification of a family of animal sphingomyelin synthases. EMBO J 23:33–44
Im YJ, Raychaudhuri S, Prinz WA, Hurley JH (2005) Structural mechanism for sterol sensing and transport by OSBP-related proteins. Nature 437:154–158
Ingmundson A, Delprato A, Lambright DG, Roy CR (2007) Legionella pneumophila proteins that regulate Rab1 membrane cycling. Nature 450:365–369
Johansson M, Lehto M, Tanhuanpaa K, Cover TL, Olkkonen VM (2005) The oxysterol-binding protein homologue ORP1L interacts with Rab7 and alters functional properties of late endocytic compartments. Mol Biol Cell 16:5480–5492
Justis AV, Hansen B, Beare PA, King KB, Heinzen RA, Gilk SD (2016) Interactions between the Coxiella burnetii parasitophorous vacuole and the endoplasmic reticulum involve the host protein ORP1L. Cell Microbiol
Khavkin T, Tabibzadeh SS (1988) Histologic, immunofluorescence, and electron microscopic study of infectious process in mouse lung after intranasal challenge with Coxiella burnetii. Infect Immun 56:1792–1799
Kornmann B (2013) The molecular hug between the ER and the mitochondria. Curr Opin Cell Biol 25:443–448
Kudo N, Kumagai K, Matsubara R, Kobayashi S, Hanada K, Wakatsuki S, Kato R (2010) Crystal structures of the CERT START domain with inhibitors provide insights into the mechanism of ceramide transfer. J Mol Biol 396:245–251
Larson CL, Beare PA, Howe D, Heinzen RA (2013) Coxiella burnetii effector protein subverts clathrin-mediated vesicular trafficking for pathogen vacuole biogenesis. Proc Natl Acad Sci USA 110:E4770–E4779
Lemmon MA (2008) Membrane recognition by phospholipid-binding domains. Nat Rev Mol Cell Biol 9:99–111
Lev S, Ben Halevy D, Peretti D, Dahan N (2008) The VAP protein family: from cellular functions to motor neuron disease. Trends Cell Biol 18:282–290
Loewen CJ, Levine TP (2005) A highly conserved binding site in vesicle-associated membrane protein-associated protein (VAP) for the FFAT motif of lipid-binding proteins. J Biol Chem 280:14097–14104
Loewen CJ, Roy A, Levine TP (2003) A conserved ER targeting motif in three families of lipid binding proteins and in Opi1p binds VAP. EMBO J 22:2025–2035
Lutter EI, Martens C, Hackstadt T (2012) Evolution and conservation of predicted inclusion membrane proteins in chlamydiae. Comp Funct Genomics 2012:362104
Machner MP, Isberg RR (2006) Targeting of host Rab GTPase function by the intravacuolar pathogen Legionella pneumophila. Dev Cell 11:47–56
Malhotra M, Sood S, Mukherjee A, Muralidhar S, Bala M (2013) Genital Chlamydia trachomatis: an update. Ind J Med Res 138:303–316
Marston BJ, Lipman HB, Breiman RF (1994) Surveillance for Legionnaires’ disease. Risk factors for morbidity and mortality. Arch Intern Med 154:2417–2422
Mehlitz A, Karunakaran K, Herweg JA, Krohne G, van de Linde S, Rieck E, Sauer M, Rudel T (2014) The chlamydial organism Simkania negevensis forms ER vacuole contact sites and inhibits ER-stress. Cell Microbiol 16:1224–1243
Moffatt JH, Newton P, Newton HJ (2015) Coxiella burnetii: turning hostility into a home. Cell Microbiol 17:621–631
Moos A, Hackstadt T (1987) Comparative virulence of intra- and interstrain lipopolysaccharide variants of Coxiella burnetii in the guinea pig model. Infect Immun 55:1144–1150
Moulder JW (1991) Interaction of chlamydiae and host cells in vitro. Microbiol Rev 55:143–190
Mueller KE, Plano GV, Fields KA (2014) New frontiers in type III secretion biology: the Chlamydia perspective. Infect Immun 82:2–9
Mukherjee S, Maxfield FR (2004) Lipid and cholesterol trafficking in NPC. Biochim Biophys Acta 1685:28–37
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
Muller 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
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
Nakatsu F, Baskin JM, Chung J, Tanner LB, Shui G, Lee SY, Pirruccello M, Hao M, Ingolia NT, Wenk MR et al (2012) PtdIns4P synthesis by PI4KIIIα at the plasma membrane and its impact on plasma membrane identity. J Cell Biol 199:1003–1016
Neunuebel MR, Chen Y, Gaspar AH, Backlund PS Jr, Yergey A, Machner MP (2011) De-AMPylation of the small GTPase Rab1 by the pathogen Legionella pneumophila. Science 333:453–456
Newton HJ, McDonough JA, Roy CR (2013) Effector protein translocation by the Coxiella burnetii Dot/Icm type IV secretion system requires endocytic maturation of the pathogen-occupied vacuole. PLoS One 8:e54566
Nguyen TM, Ilef D, Jarraud S, Rouil L, Campese C, Che D, Haeghebaert S, Ganiayre F, Marcel F, Etienne J et al (2006) A community-wide outbreak of legionnaires disease linked to industrial cooling towers – how far can contaminated aerosols spread? J Infect Dis 193:102–111
Omsland A, Cockrell DC, Howe D, Fischer ER, Virtaneva K, Sturdevant DE, Porcella SF, Heinzen RA (2009) Host cell-free growth of the Q fever bacterium Coxiella burnetii. Proc Natl Acad Sci USA 106:4430–4434
Ponting CP, Aravind L (1999) START: a lipid-binding domain in StAR, HD-ZIP and signalling proteins. Trends Biochem Sci 24:130–132
Prakriya M, Lewis RS (2015) Store-operated calcium channels. Physiol Rev 95:1383–1436
Prinz WA (2014) Bridging the gap: membrane contact sites in signaling, metabolism, and organelle dynamics. J Cell Biol 205:759–769
Riley M, Abe T, Arnaud MB, Berlyn MK, Blattner FR, Chaudhuri RR, Glasner JD, Horiuchi T, Keseler IM, Kosuge T et al (2006) Escherichia coli K-12: a cooperatively developed annotation snapshot – 2005. Nucleic Acids Res 34:1–9
Robinson CG, Roy CR (2006) Attachment and fusion of endoplasmic reticulum with vacuoles containing Legionella pneumophila. Cell Microbiol 8:793–805
Rocha N, Kuijl C, van der Kant R, Janssen L, Houben D, Janssen H, Zwart W, Neefjes J (2009) Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150 Glued and late endosome positioning. J Cell Biol 185:1209–1225
Schachter J (1999) Infection and disease epidemiology. In: Stephens RS (ed) Chlamydia: intracellular biology, pathogenesis, and immunity. American Society for Microbiology, Wahsington, DC, pp 139–170
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
Segal G, Purcell M, Shuman HA (1998) Host cell killing and bacterial conjugation require overlapping sets of genes within a 22-kb region of the Legionella pneumophila genome. Proc Natl Acad Sci USA 95:1669–1674
Seshadri R, Paulsen IT, Eisen JA, Read TD, Nelson KE, Nelson WC, Ward NL, Tettelin H, Davidsen TM, Beanan MJ et al (2003) Complete genome sequence of the Q-fever pathogen Coxiella burnetii. Proc Natl Acad Sci USA 100:5455–5460
Shima K, Klinger M, Schutze S, Kaufhold I, Solbach W, Reiling N, Rupp J (2015) The role of ER-related BiP/GRP78 in IFN-gamma induced persistent Chlamydia pneumoniae infection. Cell Microbiol 17(7):923–934
Stefan CJ, Manford AG, Baird D, Yamada-Hanff J, Mao Y, Emr SD (2011) Osh proteins regulate phosphoinositide metabolism at ER-plasma membrane contact sites. Cell 144:389–401
Stephens RS, Kalman S, Lammel C, Fan J, Marathe R, Aravind L, Mitchell W, Olinger L, Tatusov RL, Zhao Q et al (1998) Genome sequence of an obligate intracellular pathogen of humans: Chlamydia trachomatis. Science 282:754–759
Suchanek M, Hynynen R, Wohlfahrt G, Lehto M, Johansson M, Saarinen H, Radzikowska A, Thiele C, Olkkonen VM (2007) The mammalian oxysterol-binding protein-related proteins (ORPs) bind 25-hydroxycholesterol in an evolutionarily conserved pocket. Biochem J 405:473–480
Tafesse FG, Huitema K, Hermansson M, van der Poel S, van den Dikkenberg J, Uphoff A, Somerharju P, Holthuis JC (2007) Both sphingomyelin synthases SMS1 and SMS2 are required for sphingomyelin homeostasis and growth in human HeLa cells. J Biol Chem 282:17537–17547
Tan Y, Luo ZQ (2011) Legionella pneumophila SidD is a deAMPylase that modifies Rab1. Nature 475:506–509
Tan Y, Arnold RJ, Luo ZQ (2011) Legionella pneumophila regulates the small GTPase Rab1 activity by reversible phosphorylcholination. Proc Natl Acad Sci USA 108:21212–21217
Tilney LG, Harb OS, Connelly PS, Robinson CG, Roy CR (2001) How the parasitic bacterium Legionella pneumophila modifies its phagosome and transforms it into rough ER: implications for conversion of plasma membrane to the ER membrane. J Cell Sci 114:4637–4650
van Ooij C, Kalman L, van Ijzendoorn, Nishijima M, Hanada K, Mostov K, Engel JN (2000) Host cell-derived sphingolipids are required for the intracellular growth of Chlamydia trachomatis. Cell Microbiol 2:627–637
van Schaik EJ, Chen C, Mertens K, Weber MM, Samuel JE (2013) Molecular pathogenesis of the obligate intracellular bacterium Coxiella burnetii. Nat Rev Microbiol 11:561–573
Vogel JP, Andrews HL, Wong SK, Isberg RR (1998) Conjugative transfer by the virulence system of Legionella pneumophila. Science 279:873–876
Voth DE, Heinzen RA (2007) Lounging in a lysosome: the intracellular lifestyle of Coxiella burnetii. Cell Microbiol 9:829–840
Weber-Boyvat M, Kentala H, Peranen J, Olkkonen VM (2015) Ligand-dependent localization and function of ORP-VAP complexes at membrane contact sites. Cell Mol Life Sci 72:1967–1987
Wylie JL, Hatch GM, McClarty G (1997) Host cell phospholipids are trafficked to and then modified by Chlamydia trachomatis. J Bacteriol 179:7233–7242
Yasuda S, Kitagawa H, Ueno M, Ishitani H, Fukasawa M, Nishijima M, Kobayashi S, Hanada K (2001) A novel inhibitor of ceramide trafficking from the endoplasmic reticulum to the site of sphingomyelin synthesis. J Biol Chem 276:43994–44002
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
Zhu W, Banga S, Tan Y, Zheng C, Stephenson R, Gately J, Luo ZQ (2011) Comprehensive identification of protein substrates of the Dot/Icm type IV transporter of Legionella pneumophila. PLoS One 6:e17638
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Derré, I. (2017). Hijacking of Membrane Contact Sites by Intracellular Bacterial Pathogens. In: Tagaya, M., Simmen, T. (eds) Organelle Contact Sites. Advances in Experimental Medicine and Biology, vol 997. Springer, Singapore. https://doi.org/10.1007/978-981-10-4567-7_16
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