Adenylate Cyclase Toxin Mobilizes Its β Integrin Receptor into Lipid Rafts to Accomplish Translocation across Target Cell Membrane in Two Steps
Bordetella adenylate cyclase toxin (CyaA) binds the αMβ2 integrin (CD11b/CD18, Mac-1, or CR3) of myeloid phagocytes and delivers into their cytosol an adenylate cyclase (AC) enzyme that converts ATP into the key signaling molecule cAMP. We show that penetration of the AC domain across cell membrane proceeds in two steps. It starts by membrane insertion of a toxin ‘translocation intermediate’, which can be ‘locked’ in the membrane by the 3D1 antibody blocking AC domain translocation. Insertion of the ‘intermediate’ permeabilizes cells for influx of extracellular calcium ions and thus activates calpain-mediated cleavage of the talin tether. Recruitment of the integrin-CyaA complex into lipid rafts follows and the cholesterol-rich lipid environment promotes translocation of the AC domain across cell membrane. AC translocation into cells was inhibited upon raft disruption by cholesterol depletion, or when CyaA mobilization into rafts was blocked by inhibition of talin processing. Furthermore, CyaA mutants unable to mobilize calcium into cells failed to relocate into lipid rafts, and failed to translocate the AC domain across cell membrane, unless rescued by Ca2+ influx promoted in trans by ionomycin or another CyaA protein. Hence, by mobilizing calcium ions into phagocytes, the ‘translocation intermediate’ promotes toxin piggybacking on integrin into lipid rafts and enables AC enzyme delivery into host cytosol.
Vyšlo v časopise:
Adenylate Cyclase Toxin Mobilizes Its β Integrin Receptor into Lipid Rafts to Accomplish Translocation across Target Cell Membrane in Two Steps. PLoS Pathog 6(5): e32767. doi:10.1371/journal.ppat.1000901
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1000901
Souhrn
Bordetella adenylate cyclase toxin (CyaA) binds the αMβ2 integrin (CD11b/CD18, Mac-1, or CR3) of myeloid phagocytes and delivers into their cytosol an adenylate cyclase (AC) enzyme that converts ATP into the key signaling molecule cAMP. We show that penetration of the AC domain across cell membrane proceeds in two steps. It starts by membrane insertion of a toxin ‘translocation intermediate’, which can be ‘locked’ in the membrane by the 3D1 antibody blocking AC domain translocation. Insertion of the ‘intermediate’ permeabilizes cells for influx of extracellular calcium ions and thus activates calpain-mediated cleavage of the talin tether. Recruitment of the integrin-CyaA complex into lipid rafts follows and the cholesterol-rich lipid environment promotes translocation of the AC domain across cell membrane. AC translocation into cells was inhibited upon raft disruption by cholesterol depletion, or when CyaA mobilization into rafts was blocked by inhibition of talin processing. Furthermore, CyaA mutants unable to mobilize calcium into cells failed to relocate into lipid rafts, and failed to translocate the AC domain across cell membrane, unless rescued by Ca2+ influx promoted in trans by ionomycin or another CyaA protein. Hence, by mobilizing calcium ions into phagocytes, the ‘translocation intermediate’ promotes toxin piggybacking on integrin into lipid rafts and enables AC enzyme delivery into host cytosol.
Zdroje
1. FriedmanRL
FiederleinRL
GlasserL
GalgianiJN
1987 Bordetella pertussis adenylate cyclase: effects of affinity-purified adenylate cyclase on human polymorphonuclear leukocyte functions. Infect Immun 55 135 140
2. KamanovaJ
KofronovaO
MasinJ
GenthH
VojtovaJ
2008 Adenylate cyclase toxin subverts phagocyte function by RhoA inhibition and unproductive ruffling. J Immunol 181 5587 5597
3. ConferDL
EatonJW
1982 Phagocyte impotence caused by an invasive bacterial adenylate cyclase. Science 217 948 950
4. WeingartCL
WeissAA
2000 Bordetella pertussis virulence factors affect phagocytosis by human neutrophils. Infect Immun 68 1735 1739
5. GoodwinMS
WeissAA
1990 Adenylate cyclase toxin is critical for colonization and pertussis toxin is critical for lethal infection by Bordetella pertussis in infant mice. Infect Immun 58 3445 3447
6. BellalouJ
SakamotoH
LadantD
GeoffroyC
UllmannA
1990 Deletions affecting hemolytic and toxin activities of Bordetella pertussis adenylate cyclase. Infect Immun 58 3242 3247
7. BenzR
MaierE
LadantD
UllmannA
SeboP
1994 Adenylate cyclase toxin (CyaA) of Bordetella pertussis. Evidence for the formation of small ion-permeable channels and comparison with HlyA of Escherichia coli. J Biol Chem 269 27231 27239
8. BaslerM
MasinJ
OsickaR
SeboP
2006 Pore-forming and enzymatic activities of Bordetella pertussis adenylate cyclase toxin synergize in promoting lysis of monocytes. Infect Immun 74 2207 2214
9. HewlettEL
DonatoGM
GrayMC
2006 Macrophage cytotoxicity produced by adenylate cyclase toxin from Bordetella pertussis: more than just making cyclic AMP! Mol Microbiol 59 447 459
10. Vojtova-VodolanovaJ
BaslerM
OsickaR
KnappO
MaierE
2009 Oligomerization is involved in pore formation by Bordetella adenylate cyclase toxin. Faseb J 23 2831 2843
11. VojtovaJ
KamanovaJ
SeboP
2006 Bordetella adenylate cyclase toxin: a swift saboteur of host defense. Curr Opin Microbiol 9 69 75
12. HackettM
GuoL
ShabanowitzJ
HuntDF
HewlettEL
1994 Internal lysine palmitoylation in adenylate cyclase toxin from Bordetella pertussis. Science 266 433 435
13. HackettM
WalkerCB
GuoL
GrayMC
Van CuykS
1995 Hemolytic, but not cell-invasive activity, of adenylate cyclase toxin is selectively affected by differential fatty-acylation in Escherichia coli. J Biol Chem 270 20250 20253
14. RoseT
SeboP
BellalouJ
LadantD
1995 Interaction of calcium with Bordetella pertussis adenylate cyclase toxin. Characterization of multiple calcium-binding sites and calcium-induced conformational changes. J Biol Chem 270 26370 26376
15. GordonVM
LepplaSH
HewlettEL
1988 Inhibitors of receptor-mediated endocytosis block the entry of Bacillus anthracis adenylate cyclase toxin but not that of Bordetella pertussis adenylate cyclase toxin. Infect Immun 56 1066 1069
16. GmiraS
KarimovaG
LadantD
2001 Characterization of recombinant Bordetella pertussis adenylate cyclase toxins carrying passenger proteins. Res Microbiol 152 889 900
17. OteroAS
YiXB
GrayMC
SzaboG
HewlettEL
1995 Membrane depolarization prevents cell invasion by Bordetella pertussis adenylate cyclase toxin. J Biol Chem 270 9695 9697
18. FiserR
MasinJ
BaslerM
KrusekJ
SpulakovaV
2007 Third activity of Bordetella adenylate cyclase (AC) toxin-hemolysin. Membrane translocation of AC domain polypeptide promotes calcium influx into CD11b+ monocytes independently of the catalytic and hemolytic activities. J Biol Chem 282 2808 2820
19. BaslerM
KnappO
MasinJ
FiserR
MaierE
2007 Segments crucial for membrane translocation and pore-forming activity of Bordetella adenylate cyclase toxin. J Biol Chem 282 12419 12429
20. OsickovaA
OsickaR
MaierE
BenzR
SeboP
1999 An amphipathic alpha-helix including glutamates 509 and 516 is crucial for membrane translocation of adenylate cyclase toxin and modulates formation and cation selectivity of its membrane channels. J Biol Chem 274 37644 37650
21. LadantD
UllmannA
1999 Bordatella pertussis adenylate cyclase: a toxin with multiple talents. Trends Microbiol 7 172 176
22. PaccaniSR
Dal MolinF
BenagianoM
LadantD
D'EliosMM
2008 Suppression of T-lymphocyte activation and chemotaxis by the adenylate cyclase toxin of Bordetella pertussis. Infect Immun 76 2822 2832
23. GordonVM
YoungWWJr
LechlerSM
GrayMC
LepplaSH
1989 Adenylate cyclase toxins from Bacillus anthracis and Bordetella pertussis. Different processes for interaction with and entry into target cells. J Biol Chem 264 14792 14796
24. MorovaJ
OsickaR
MasinJ
SeboP
2008 RTX cytotoxins recognize beta2 integrin receptors through N-linked oligosaccharides. Proc Natl Acad Sci U S A 105 5355 5360
25. HarrisES
McIntyreTM
PrescottSM
ZimmermanGA
2000 The leukocyte integrins. J Biol Chem 275 23409 23412
26. HynesRO
2002 Integrins: bidirectional, allosteric signaling machines. Cell 110 673 687
27. LeitingerB
HoggN
2002 The involvement of lipid rafts in the regulation of integrin function. J Cell Sci 115 963 972
28. KraussK
AltevogtP
1999 Integrin leukocyte function-associated antigen-1-mediated cell binding can be activated by clustering of membrane rafts. J Biol Chem 274 36921 36927
29. StefanovaI
HorejsiV
AnsoteguiIJ
KnappW
StockingerH
1991 GPI-anchored cell-surface molecules complexed to protein tyrosine kinases. Science 254 1016 1019
30. SimonsK
IkonenE
1997 Functional rafts in cell membranes. Nature 387 569 572
31. BrownDA
2006 Lipid rafts, detergent-resistant membranes, and raft targeting signals. Physiology (Bethesda) 21 430 439
32. JacobsonK
MouritsenOG
AndersonRG
2007 Lipid rafts: at a crossroad between cell biology and physics. Nat Cell Biol 9 7 14
33. HelmsJB
ZurzoloC
2004 Lipids as targeting signals: lipid rafts and intracellular trafficking. Traffic 5 247 254
34. LafontF
van der GootFG
2005 Bacterial invasion via lipid rafts. Cell Microbiol 7 613 620
35. ManesS
del RealG
MartinezAC
2003 Pathogens: raft hijackers. Nat Rev Immunol 3 557 568
36. FivazM
AbramiL
van der GootFG
1999 Landing on lipid rafts. Trends Cell Biol 9 212 213
37. LeeSJ
GrayMC
GuoL
SeboP
HewlettEL
1999 Epitope mapping of monoclonal antibodies against Bordetella pertussis adenylate cyclase toxin. Infect Immun 67 2090 2095
38. RogelA
HanskiE
1992 Distinct steps in the penetration of adenylate cyclase toxin of Bordetella pertussis into sheep erythrocytes. Translocation of the toxin across the membrane. J Biol Chem 267 22599 22605
39. GrayMC
LeeSJ
GrayLS
ZaretzkyFR
OteroAS
2001 Translocation-specific conformation of adenylate cyclase toxin from Bordetella pertussis inhibits toxin-mediated hemolysis. J Bacteriol 183 5904 5910
40. SampathR
GallagherPJ
PavalkoFM
1998 Cytoskeletal interactions with the leukocyte integrin beta2 cytoplasmic tail. Activation-dependent regulation of associations with talin and alpha-actinin. J Biol Chem 273 33588 33594
41. StewartMP
McDowallA
HoggN
1998 LFA-1-mediated adhesion is regulated by cytoskeletal restraint and by a Ca2+-dependent protease, calpain. J Cell Biol 140 699 707
42. GuermonprezP
KhelefN
BlouinE
RieuP
Ricciardi-CastagnoliP
2001 The adenylate cyclase toxin of Bordetella pertussis binds to target cells via the alpha(M)beta(2) integrin (CD11b/CD18). J Exp Med 193 1035 1044
43. VangT
TorgersenKM
SundvoldV
SaxenaM
LevyFO
2001 Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. J Exp Med 193 497 507
44. WilloughbyD
WongW
SchaackJ
ScottJD
CooperDM
2006 An anchored PKA and PDE4 complex regulates subplasmalemmal cAMP dynamics. Embo J 25 2051 2061
45. TaskenK
StokkaAJ
2006 The molecular machinery for cAMP-dependent immunomodulation in T-cells. Biochem Soc Trans 34 476 479
46. SteedLL
AkporiayeET
FriedmanRL
1992 Bordetella pertussis induces respiratory burst activity in human polymorphonuclear leukocytes. Infect Immun 60 2101 2105
47. LafontF
AbramiL
van der GootFG
2004 Bacterial subversion of lipid rafts. Curr Opin Microbiol 7 4 10
48. PartonRG
1994 Ultrastructural localization of gangliosides; GM1 is concentrated in caveolae. J Histochem Cytochem 42 155 166
49. FivazM
VilboisF
ThurnheerS
PasqualiC
AbramiL
2002 Differential sorting and fate of endocytosed GPI-anchored proteins. Embo J 21 3989 4000
50. WaheedAA
ShimadaY
HeijnenHF
NakamuraM
InomataM
2001 Selective binding of perfringolysin O derivative to cholesterol-rich membrane microdomains (rafts). Proc Natl Acad Sci U S A 98 4926 4931
51. OsickovaA
MasinJ
FayolleC
KrusekJ
BaslerM
2010 Adenylate cyclase toxin translocates across target cell membrane without forming a pore. Mol Microbiol 75 1550 1562
52. VojtovaJ
KofronovaO
SeboP
BenadaO
2006 Bordetella adenylate cyclase toxin induces a cascade of morphological changes of sheep erythrocytes and localizes into clusters in erythrocyte membranes. Microsc Res Tech 69 119 129
53. MartinC
RequeroMA
MasinJ
KonopasekI
GoniFM
2004 Membrane restructuring by Bordetella pertussis adenylate cyclase toxin, a member of the RTX toxin family. J Bacteriol 186 3760 3765
54. AhmedSN
BrownDA
LondonE
1997 On the origin of sphingolipid/cholesterol-rich detergent-insoluble cell membranes: physiological concentrations of cholesterol and sphingolipid induce formation of a detergent-insoluble, liquid-ordered lipid phase in model membranes. Biochemistry 36 10944 10953
55. SilviusJR
del GiudiceD
LafleurM
1996 Cholesterol at different bilayer concentrations can promote or antagonize lateral segregation of phospholipids of differing acyl chain length. Biochemistry 35 15198 15208
56. ScottoAW
ZakimD
1986 Reconstitution of membrane proteins: catalysis by cholesterol of insertion of integral membrane proteins into preformed lipid bilayers. Biochemistry 25 1555 1561
57. GollDE
ThompsonVF
LiH
WeiW
CongJ
2003 The calpain system. Physiol Rev 83 731 801
58. FongKP
PachecoCM
OtisLL
BaranwalS
KiebaIR
2006 Actinobacillus actinomycetemcomitans leukotoxin requires lipid microdomains for target cell cytotoxicity. Cell Microbiol 8 1753 1767
59. DaviesEV
HallettMB
1998 High micromolar Ca2+ beneath the plasma membrane in stimulated neutrophils. Biochem Biophys Res Commun 248 679 683
60. FrankenKL
HiemstraHS
van MeijgaardenKE
SubrontoY
den HartighJ
2000 Purification of his-tagged proteins by immobilized chelate affinity chromatography: the benefits from the use of organic solvent. Protein Expr Purif 18 95 99
61. LadantD
1988 Interaction of Bordetella pertussis adenylate cyclase with calmodulin. Identification of two separated calmodulin-binding domains. J Biol Chem 263 2612 2618
62. KarimovaG
FayolleC
GmiraS
UllmannA
LeclercC
1998 Charge-dependent translocation of Bordetella pertussis adenylate cyclase toxin into eukaryotic cells: implication for the in vivo delivery of CD8(+) T cell epitopes into antigen-presenting cells. Proc Natl Acad Sci U S A 95 12532 12537
63. OsickaR
OsickovaA
BasarT
GuermonprezP
RojasM
2000 Delivery of CD8(+) T-cell epitopes into major histocompatibility complex class I antigen presentation pathway by Bordetella pertussis adenylate cyclase: delineation of cell invasive structures and permissive insertion sites. Infect Immun 68 247 256
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2010 Číslo 5
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Quorum Sensing Inhibition Selects for Virulence and Cooperation in
- The Role of Intestinal Microbiota in the Development and Severity of Chemotherapy-Induced Mucositis
- Susceptibility to Anthrax Lethal Toxin-Induced Rat Death Is Controlled by a Single Chromosome 10 Locus That Includes
- Demonstration of Cross-Protective Vaccine Immunity against an Emerging Pathogenic Ebolavirus Species