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Host Lipidation: A Mechanism for Spatial Regulation of Legionella Effectors

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Molecular Mechanisms in Legionella Pathogenesis

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 376))

Abstract

Bacterial pathogens have evolved the capacity to translocate proteins into the cytosol of infected cells to manipulate host processes. How do pathogens regulate spatially these bacterial effector proteins once they are released into the host cell? One mechanism, which is used by Legionella and other bacterial pathogens, is to encode effectors that mimic the substrates of eukaryotic lipid transferases. In this review we discuss three membrane-targeting pathways in eukaryotes that are exploited by Legionella and other pathogens—prenylation, palmitoylation, and myristoylation. Lipidation of bacterial substrates primes the effectors for coincidence detection-mediated targeting onto membrane-bound organelles by increasing membrane affinity. Intracellular membrane-targeting strategies that exploit protein fatty acylation and prenylation direct bacterial effectors to compartments where their target substrates reside and thus are critical for effector function.

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Abbreviations

CaaX motif:

Cysteine-aliphatic-aliphatic-X amino acid motif

cAMP:

cyclic AMP

CMPs:

CaaX motif-containing proteins

Dot/Icm:

Defect in organelle trafficking/intracellular multiplication

DHHC PATs:

Asp-His-His-Cys palmitoyl acyltransferases

FTase:

Farnesyltransferase

GEFs:

Guanine nucleotide exchange factors

GGTase:

Geranylgeranyltransferase

HR:

Hypersensitivity response

LCV:

Legionella-containing vacuole

NMT:

N-myristoyltransferase

PATs:

Palmitoyl acyltransferases

SCV:

Salmonella-containing vacuole

T3SS:

Type III secretion system

T4SS:

Type IV secretion system

References

  • Al-Khodor S, Price CT, Habyarimana F, Kalia A, Abu Kwaik Y (2008) A Dot/Icm-translocated ankyrin protein of Legionella pneumophila is required for intracellular proliferation within human macrophages and protozoa. Mol Microbiol 70:908–923

    PubMed  CAS  Google Scholar 

  • Alexandrov K, Horiuchi H, Steele-Mortimer O, Seabra MC, Zerial M (1994) Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes. EMBO J 13:5262–5273

    PubMed  CAS  Google Scholar 

  • Bakowski MA, Braun V, Brumell JH (2008) Salmonella-containing vacuoles: directing traffic and nesting to grow. Traffic 9:2022–2031

    Article  PubMed  CAS  Google Scholar 

  • Bergo MO, Leung GK, Ambroziak P, Otto JC, Casey PJ, Young SG (2000) Targeted inactivation of the isoprenylcysteine carboxyl methyltransferase gene causes mislocalization of K-Ras in mammalian cells. J Biol Chem 275:17605–17610

    Article  PubMed  CAS  Google Scholar 

  • Bivona TG, Quatela SE, Bodemann BO, Ahearn IM, Soskis MJ, Mor A, Miura J, Wiener HH, Wright L, Saba SG, Yim D, Fein A, Perez de Castro I, Li C, Thompson CB, Cox AD, Philips MR (2006) PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis. Mol Cell 21:481–493

    Article  PubMed  CAS  Google Scholar 

  • Blumer J, Rey J, Dehmelt L, Mazel T, Wu YW, Bastiaens P, Goody RS, Itzen A (2013) RabGEFs are a major determinant for specific Rab membrane targeting. J Cell Biol 200:287–300

    Article  PubMed  Google Scholar 

  • Bohdanowicz M, Grinstein S (2013) Role of phospholipids in endocytosis, phagocytosis, and macropinocytosis. Physiol Rev 93:69–106

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Carlton JG, Cullen PJ (2005) Coincidence detection in phosphoinositide signaling. Trends Cell Biol 15:540–547

    Article  PubMed  CAS  Google Scholar 

  • Cho W, Stahelin RV (2005) Membrane-protein interactions in cell signaling and membrane trafficking. Annu Rev Biophys Biomol Struct 34:119–151

    Article  PubMed  CAS  Google Scholar 

  • Di Paolo G, De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–657

    Article  PubMed  Google Scholar 

  • Dowen RH, Engel JL, Shao F, Ecker JR, Dixon JE (2009) A family of bacterial cysteine protease type III effectors utilizes acylation-dependent and -independent strategies to localize to plasma membranes. J Biol Chem 284:15867–15879

    Article  PubMed  CAS  Google Scholar 

  • El-Husseini Ael D, Schnell E, Dakoji S, Sweeney N, Zhou Q, Prange O, Gauthier-Campbell C, Aguilera-Moreno A, Nicoll RA, Bredt DS (2002) Synaptic strength regulated by palmitate cycling on PSD-95. Cell 108:849–863

    Article  Google Scholar 

  • Ensminger AW, Isberg RR (2009) Legionella pneumophila Dot/Icm translocated substrates: a sum of parts. Curr Opin Microbiol 12:67–73

    Article  PubMed  CAS  Google Scholar 

  • Ensminger AW, Isberg RR (2010) E3 ubiquitin ligase activity and targeting of BAT3 by multiple Legionella pneumophila translocated substrates. Infect Immun 78:3905–3919

    Article  PubMed  CAS  Google Scholar 

  • Farazi TA, Waksman G, Gordon JI (2001) The biology and enzymology of protein N-myristoylation. J Biol Chem 276:39501–39504

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Hernando C, Fukata M, Bernatchez PN, Fukata Y, Lin MI, Bredt DS, Sessa WC (2006) Identification of Golgi-localized acyl transferases that palmitoylate and regulate endothelial nitric oxide synthase. J Cell Biol 174:369–377

    Article  PubMed  CAS  Google Scholar 

  • Fivaz M, Meyer T (2005) Reversible intracellular translocation of KRas but not HRas in hippocampal neurons regulated by Ca2 +/calmodulin. J Cell Biol 170:429–441

    Article  PubMed  CAS  Google Scholar 

  • Fukata Y, Bredt DS, Fukata M (2006) Protein palmitoylation by DHHC protein family. In: Kittler JT, Moss SJ (eds) The dynamic synapse: molecular methods in ionotropic receptor biology. CRC Press, Boca Raton

    Google Scholar 

  • Galan JE, Wolf-Watz H (2006) Protein delivery into eukaryotic cells by type III secretion machines. Nature 444:567–573

    Article  PubMed  CAS  Google Scholar 

  • Grant SR, Fisher EJ, Chang JH, Mole BM, Dangl JL (2006) Subterfuge and manipulation: type III effector proteins of phytopathogenic bacteria. Annu Rev Microbiol 60:425–449

    Article  PubMed  CAS  Google Scholar 

  • Greaves J, Chamberlain LH (2011) DHHC palmitoyl transferases: substrate interactions and (patho)physiology. Trends Biochem Sci 36:245–253

    Article  PubMed  CAS  Google Scholar 

  • Hicks SW, Charron G, Hang HC, Galan JE (2011) Subcellular targeting of Salmonella virulence proteins by host-mediated S-palmitoylation. Cell Host Microbe 10:9–20

    Article  PubMed  CAS  Google Scholar 

  • Hubber A, Roy CR (2010) Modulation of host cell function by Legionella pneumophila type IV effectors. Annu Rev Cell Dev Biol 26:261–283

    Article  PubMed  CAS  Google Scholar 

  • Hutagalung AH, Novick PJ (2011) Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev 91:119–149

    Article  PubMed  CAS  Google Scholar 

  • Ivanov SS, Charron G, Hang HC, Roy CR (2010) Lipidation by the host prenyltransferase machinery facilitates membrane localization of Legionella pneumophila effector proteins. J Biol Chem 285:34686–34698

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Jean S, Kiger AA (2012) Coordination between RAB GTPase and phosphoinositide regulation and functions. Nat Rev Mol Cell Biol 13:463–470

    Article  PubMed  CAS  Google Scholar 

  • Kim E, Ambroziak P, Otto JC, Taylor B, Ashby M, Shannon K, Casey PJ, Young SG (1999) Disruption of the mouse Rce1 gene results in defective Ras processing and mislocalization of Ras within cells. J Biol Chem 274:8383–8390

    Article  PubMed  CAS  Google Scholar 

  • Kleuss C, Krause E (2003) Galpha(s) is palmitoylated at the N-terminal glycine. EMBO J 22:826–832

    Article  PubMed  CAS  Google Scholar 

  • Konstantinopoulos PA, Karamouzis MV, Papavassiliou AG (2007) Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets. Nat Rev Drug Discov 6:541–555

    Article  PubMed  CAS  Google Scholar 

  • Krauss M, Haucke V (2007) Phosphoinositides: regulators of membrane traffic and protein function. FEBS Lett 581:2105–2111

    Article  PubMed  CAS  Google Scholar 

  • Kutateladze TG (2010) Translation of the phosphoinositide code by PI effectors. Nat Chem Biol 6:507–513

    Article  PubMed  CAS  Google Scholar 

  • Ladant D, Ullmann A (1999) Bordatella pertussis adenylate cyclase: a toxin with multiple talents. Trends Microbiol 7:172–176

    Article  PubMed  CAS  Google Scholar 

  • Lomma M, Dervins-Ravault D, Rolando M, Nora T, Newton HJ, Sansom FM, Sahr T, Gomez-Valero L, Jules M, Hartland EL, Buchrieser C (2010) The Legionella pneumophila F-box protein Lpp 2082 (AnkB) modulates ubiquitination of the host protein parvin B and promotes intracellular replication. Cell Microbiol 12:1272–1291

    Article  PubMed  CAS  Google Scholar 

  • Machner MP, Isberg RR (2006) Targeting of host Rab GTPase function by the intravacuolar pathogen Legionella pneumophila. Dev Cell 11:47–56

    Article  PubMed  CAS  Google Scholar 

  • McGourty K, Thurston TL, Matthews SA, Pinaud L, Mota LJ, Holden DW (2012) Salmonella inhibits retrograde trafficking of mannose-6-phosphate receptors and lysosome function. Science 338:963–967

    Article  PubMed  CAS  Google Scholar 

  • McLaughlin LM, Govoni GR, Gerke C, Gopinath S, Peng K, Laidlaw G, Chien YH, Jeong HW, Li Z, Brown MD, Sacks DB, Monack D (2009) The Salmonella SPI2 effector SseI mediates long-term systemic infection by modulating host cell migration. PLoS Pathog 5:e1000671

    Article  PubMed  Google Scholar 

  • Mizuno-Yamasaki E, Rivera-Molina F, Novick P (2012) GTPase networks in membrane traffic. Annu Rev Biochem 81:637–659

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Nimchuk Z, Marois E, Kjemtrup S, Leister RT, Katagiri F, Dangl JL (2000) Eukaryotic fatty acylation drives plasma membrane targeting and enhances function of several type III effector proteins from Pseudomonas syringae. Cell 101:353–363

    Article  PubMed  CAS  Google Scholar 

  • Ninio S, Celli J, Roy CR (2009) A Legionella pneumophila effector protein encoded in a region of genomic plasticity binds to Dot/Icm-modified vacuoles. PLoS Pathog 5:e1000278

    Article  PubMed  Google Scholar 

  • 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 U S A 108:14733–14740

    Article  PubMed  Google Scholar 

  • Ohlson MB, Huang Z, Alto NM, Blanc MP, Dixon JE, Chai J, Miller SI (2008) Structure and function of Salmonella SifA indicate that its interactions with SKIP, SseJ, and RhoA family GTPases induce endosomal tubulation. Cell Host Microbe 4:434–446

    Article  PubMed  CAS  Google Scholar 

  • Peitzsch RM, McLaughlin S (1993) Binding of acylated peptides and fatty acids to phospholipid vesicles: pertinence to myristoylated proteins. Biochemistry 32:10436–10443

    Article  PubMed  CAS  Google Scholar 

  • Price CT, Al-Khodor S, Al-Quadan T, Santic M, Habyarimana F, Kalia A, Kwaik YA (2009) Molecular mimicry by an F-box effector of Legionella pneumophila hijacks a conserved polyubiquitination machinery within macrophages and protozoa. PLoS Pathog 5:e1000704

    Article  PubMed  Google Scholar 

  • Price CT, Al-Quadan T, Santic M, Jones SC, Abu Kwaik Y (2010a) Exploitation of conserved eukaryotic host cell farnesylation machinery by an F-box effector of Legionella pneumophila. J Exp Med 207:1713–1726

    Article  PubMed  CAS  Google Scholar 

  • Price CT, Jones SC, Amundson KE, Kwaik YA (2010b) Host-mediated post-translational prenylation of novel dot/icm-translocated effectors of legionella pneumophila. Front Microbiol 1:131

    PubMed  CAS  Google Scholar 

  • Qanbar R, Bouvier M (2003) Role of palmitoylation/depalmitoylation reactions in G-protein-coupled receptor function. Pharmacol Ther 97:1–33

    Article  PubMed  CAS  Google Scholar 

  • Quezada CM, Hicks SW, Galan JE, Stebbins CE (2009) A family of Salmonella virulence factors functions as a distinct class of autoregulated E3 ubiquitin ligases. Proc Natl Acad Sci U S A 106:4864–4869

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Reinicke AT, Hutchinson JL, Magee AI, Mastroeni P, Trowsdale J, Kelly AP (2005) A Salmonella typhimurium effector protein SifA is modified by host cell prenylation and S-acylation machinery. J Biol Chem 280:14620–14627

    Article  PubMed  CAS  Google Scholar 

  • Resh MD (2006) Trafficking and signaling by fatty-acylated and prenylated proteins. Nat Chem Biol 2:584–590

    Article  PubMed  CAS  Google Scholar 

  • Rocks O, Peyker A, Kahms M, Verveer PJ, Koerner C, Lumbierres M, Kuhlmann J, Waldmann H, Wittinghofer A, Bastiaens PI (2005) An acylation cycle regulates localization and activity of palmitoylated Ras isoforms. Science 307:1746–1752

    Article  PubMed  CAS  Google Scholar 

  • Schmidt WK, Tam A, Fujimura-Kamada K, Michaelis S (1998) Endoplasmic reticulum membrane localization of Rce1p and Ste24p, yeast proteases involved in carboxyl-terminal CAAX protein processing and amino-terminal a-factor cleavage. Proc Natl Acad Sci U S A 95:11175–11180

    Article  PubMed  CAS  Google Scholar 

  • Sebti SM (2005) Protein farnesylation: implications for normal physiology, malignant transformation, and cancer therapy. Cancer Cell 7:297–300

    Article  PubMed  CAS  Google Scholar 

  • Shao F, Golstein C, Ade J, Stoutemyer M, Dixon JE, Innes RW (2003) Cleavage of Arabidopsis PBS1 by a bacterial type III effector. Science 301:1230–1233

    Article  PubMed  CAS  Google Scholar 

  • Shao F, Merritt PM, Bao Z, Innes RW, Dixon JE (2002) A Yersinia effector and a Pseudomonas avirulence protein define a family of cysteine proteases functioning in bacterial pathogenesis. Cell 109:575–588

    Article  PubMed  CAS  Google Scholar 

  • Silvius JR, l’Heureux F (1994) Fluorimetric evaluation of the affinities of isoprenylated peptides for lipid bilayers. Biochemistry 33:3014–3022

    Article  PubMed  CAS  Google Scholar 

  • Smotrys JE, Linder ME (2004) Palmitoylation of intracellular signaling proteins: regulation and function. Annu Rev Biochem 73:559–587

    Article  PubMed  CAS  Google Scholar 

  • Voth DE, Broederdorf LJ, Graham JG (2012) Bacterial Type IV secretion systems: versatile virulence machines. Future Microbiol 7:241–257

    Article  PubMed  CAS  Google Scholar 

  • Yamasaki A, Menon S, Yu S, Barrowman J, Meerloo T, Oorschot V, Klumperman J, Satoh A, Ferro-Novick S (2009) mTrs130 is a component of a mammalian TRAPPII complex, a Rab1 GEF that binds to COPI-coated vesicles. Mol Biol Cell 20:4205–4215

    Article  PubMed  CAS  Google Scholar 

  • Yang SH, Shrivastav A, Kosinski C, Sharma RK, Chen MH, Berthiaume LG, Peters LL, Chuang PT, Young SG, Bergo MO (2005) N-myristoyltransferase 1 is essential in early mouse development. J Biol Chem 280:18990–18995

    Article  PubMed  CAS  Google Scholar 

  • Yeung T, Gilbert GE, Shi J, Silvius J, Kapus A, Grinstein S (2008) Membrane phosphatidylserine regulates surface charge and protein localization. Science 319:210–213

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Microbial Pathogenesis, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Ave, New Haven, CT, 06519, USA

    Stanimir S. Ivanov & Craig Roy

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  1. Stanimir S. Ivanov
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  2. Craig Roy
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Correspondence to Craig Roy .

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Editors and Affiliations

  1. Max von Pettenkofer Institute, Ludwig-Maximilians University MĂĽnchen, Munich, Germany

    Hubert Hilbi

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Ivanov, S.S., Roy, C. (2013). Host Lipidation: A Mechanism for Spatial Regulation of Legionella Effectors. In: Hilbi, H. (eds) Molecular Mechanisms in Legionella Pathogenesis. Current Topics in Microbiology and Immunology, vol 376. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2013_344

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