A Toxin that Hijacks the Host Ubiquitin Proteolytic System


Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen chronically infecting the lungs of patients with chronic obstructive pulmonary disease (COPD), pneumonia, cystic fibrosis (CF), and bronchiectasis. Cif (PA2934), a bacterial toxin secreted in outer membrane vesicles (OMV) by P. aeruginosa, reduces CFTR-mediated chloride secretion by human airway epithelial cells, a key driving force for mucociliary clearance. The aim of this study was to investigate the mechanism whereby Cif reduces CFTR-mediated chloride secretion. Cif redirected endocytosed CFTR from recycling endosomes to lysosomes by stabilizing an inhibitory effect of G3BP1 on the deubiquitinating enzyme (DUB), USP10, thereby reducing USP10-mediated deubiquitination of CFTR and increasing the degradation of CFTR in lysosomes. This is the first example of a bacterial toxin that regulates the activity of a host DUB. These data suggest that the ability of P. aeruginosa to chronically infect the lungs of patients with COPD, pneumonia, CF, and bronchiectasis is due in part to the secretion of OMV containing Cif, which inhibits CFTR-mediated chloride secretion and thereby reduces the mucociliary clearance of pathogens.


Vyšlo v časopise: A Toxin that Hijacks the Host Ubiquitin Proteolytic System. PLoS Pathog 7(3): e32767. doi:10.1371/journal.ppat.1001325
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001325

Souhrn

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen chronically infecting the lungs of patients with chronic obstructive pulmonary disease (COPD), pneumonia, cystic fibrosis (CF), and bronchiectasis. Cif (PA2934), a bacterial toxin secreted in outer membrane vesicles (OMV) by P. aeruginosa, reduces CFTR-mediated chloride secretion by human airway epithelial cells, a key driving force for mucociliary clearance. The aim of this study was to investigate the mechanism whereby Cif reduces CFTR-mediated chloride secretion. Cif redirected endocytosed CFTR from recycling endosomes to lysosomes by stabilizing an inhibitory effect of G3BP1 on the deubiquitinating enzyme (DUB), USP10, thereby reducing USP10-mediated deubiquitination of CFTR and increasing the degradation of CFTR in lysosomes. This is the first example of a bacterial toxin that regulates the activity of a host DUB. These data suggest that the ability of P. aeruginosa to chronically infect the lungs of patients with COPD, pneumonia, CF, and bronchiectasis is due in part to the secretion of OMV containing Cif, which inhibits CFTR-mediated chloride secretion and thereby reduces the mucociliary clearance of pathogens.


Zdroje

1. MizgerdJP

2006

Lung infection–a public health priority.

PLoS Med

3

e76

2. BombergerJM

MaceachranDP

CoutermarshBA

YeS

O'TooleGA

2009

Long-distance delivery of bacterial virulence factors by Pseudomonas aeruginosa outer membrane vesicles.

PLoS Pathog

5

e1000382

3. Swiatecka-UrbanA

Moreau-MarquisS

MaceachranDP

ConnollyJP

StantonCR

2006

Pseudomonas aeruginosa inhibits endocytic recycling of CFTR in polarized human airway epithelial cells.

Am J Physiol Cell Physiol

290

C862

872

4. MacEachranDP

YeS

BombergerJM

HoganDA

Swiatecka-UrbanA

2007

The Pseudomonas aeruginosa secreted protein PA2934 decreases apical membrane expression of the cystic fibrosis transmembrane conductance regulator.

Infect Immun

75

3902

3912

5. MacEachranDP

StantonBA

O'TooleGA

2008

Cif is negatively regulated by the TetR family repressor CifR.

Infect Immun

76

3197

3206

6. RytkonenA

HoldenDW

2007

Bacterial interference of ubiquitination and deubiquitination.

Cell Host Microbe

1

13

22

7. EdelmannMJ

KesslerBM

2008

Ubiquitin and ubiquitin-like specific proteases targeted by infectious pathogens: Emerging patterns and molecular principles.

Biochim Biophys Acta

1782

809

816

8. AngotA

VergunstA

GeninS

PeetersN

2007

Exploitation of eukaryotic ubiquitin signaling pathways by effectors translocated by bacterial type III and type IV secretion systems.

PLoS Pathog

3

e3

9. BalachandranP

DragoneL

Garrity-RyanL

LemusA

WeissA

2007

The ubiquitin ligase Cbl-b limits Pseudomonas aeruginosa exotoxin T-mediated virulence.

J Clin Invest

117

419

427

10. BombergerJM

BarnabyRL

StantonBA

2009

The Deubiquitinating Enzyme USP10 Regulates the Post-endocytic Sorting of Cystic Fibrosis Transmembrane Conductance Regulator in Airway Epithelial Cells.

J Biol Chem

284

18778

18789

11. HoibyN

KochC

FrederiksenB

1998

[Cystic fibrosis].

Nord Med

113

328

330

12. Swiatecka-UrbanA

TalebianL

KannoE

Moreau-MarquisS

CoutermarshB

2007

Myosin VB is required for trafficking of CFTR in RAB11A-specific apical recycling endosomes in polarized human airway epithelial cells.

J Biol Chem Aug 10;

282

32

23725

36

13. Swiatecka-UrbanA

BrownA

Moreau-MarquisS

RenukaJ

CoutermarshB

2005

The short apical membrane half-life of rescued ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR) results from accelerated endocytosis of ΔF508-CFTR in polarized human airway epithelial cells.

J Biol Chem

280

36762

36772

14. GentzschM

ChangXB

CuiL

WuY

OzolsVV

2004

Endocytic trafficking routes of wild type and ΔF508 cystic fibrosis transmembrane conductance regulator.

Mol Biol Cell

15

2684

2696

15. AmeenN

ApodacaG

2007

Defective CFTR apical endocytosis and enterocyte brush border in myosin VI-deficient mice.

Traffic

8

998

1006

16. SilvisMR

BertrandCA

AmeenN

Golin-BiselloF

ButterworthMB

2009

Rab11b regulates the apical recycling of the cystic fibrosis transmembrane conductance regulator in polarized intestinal epithelial cells.

Mol Biol Cell

20

2337

2350

17. BilanF

ThoreauV

NacferM

DerandR

NorezC

2004

Syntaxin 8 impairs trafficking of cystic fibrosis transmembrane conductance regulator (CFTR) and inhibits its channel activity.

J Cell Sci

117

1923

1935

18. BilanF

NacferM

FresquetF

NorezC

MelinP

2008

Endosomal SNARE proteins regulate CFTR activity and trafficking in epithelial cells.

Exp Cell Res

314

2199

2211

19. SharmaM

PampinellaF

NemesC

BenharougaM

SoJ

2004

Misfolding diverts CFTR from recycling to degradation: quality control at early endosomes.

J Cell Biol

164

923

933

20. BorodovskyA

OvaaH

KolliN

Gan-ErdeneT

WilkinsonKD

2002

Chemistry-based functional proteomics reveals novel members of the deubiquitinating enzyme family.

Chem Biol

9

1149

1159

21. LoveKR

CaticA

SchliekerC

PloeghHL

2007

Mechanisms, biology and inhibitors of deubiquitinating enzymes.

Nat Chem Biol

3

697

705

22. SchliekerC

WeihofenWA

FrijnsE

KattenhornLM

GaudetR

2007

Structure of a herpesvirus-encoded cysteine protease reveals a unique class of deubiquitinating enzymes.

Mol Cell

25

677

687

23. SonciniC

BerdoI

DraettaG

2001

Ras-GAP SH3 domain binding protein (G3BP) is a modulator of USP10, a novel human ubiquitin specific protease.

Oncogene

20

3869

3879

24. CohenM

StutzF

DargemontC

2003

Deubiquitination, a new player in Golgi to endoplasmic reticulum retrograde transport.

J Biol Chem

278

51989

51992

25. CohenM

StutzF

BelgarehN

Haguenauer-TsapisR

DargemontC

2003

Ubp3 requires a cofactor, Bre5, to specifically de-ubiquitinate the COPII protein, Sec23.

Nat Cell Biol

5

661

667

26. KerppolaTK

2006

Design and implementation of bimolecular fluorescence complementation (BiFC) assays for the visualization of protein interactions in living cells.

Nat Protoc

1

1278

1286

27. NagyV

DikicI

2010

Ubiquitin ligase complexes: from substrate selectivity to conjugational specificity.

Biol Chem

391

163

169

28. CaohuyH

JozwikC

PollardHB

2009

Rescue of DeltaF508-CFTR by the SGK1/Nedd4-2 signaling pathway.

J Biol Chem

284

25241

25253

29. YeS

CihilK

Beer StolzD

PilewskiJM

StantonBA

2010

C-CBL facilitates endocytosis and lysosomal degradation of CFTR in human airway epithelial cells.

J Biol Chem Sep

295

C807

18

30. BombergerJM

BarnabyRL

StantonBA

2010

The deubiquitinating enzyme USP10 regulates the endocytic recycling of CFTR in airway epithelial cells.

Channels (Austin)

4

150

154

31. ShamesSR

AuweterSD

FinlayBB

2009

Co-evolution and exploitation of host cell signaling pathways by bacterial pathogens.

Int J Biochem Cell Biol

41

380

389

32. MukherjeeS

KeitanyG

LiY

WangY

BallHL

2006

Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation.

Science

312

1211

1214

33. MittalR

Peak-ChewSY

McMahonHT

2006

Acetylation of MEK2 and I kappa B kinase (IKK) activation loop residues by YopJ inhibits signaling.

Proc Natl Acad Sci U S A

103

18574

18579

34. ZhouL

TanA

HershensonMB

2004

Yersinia YopJ inhibits pro-inflammatory molecule expression in human bronchial epithelial cells.

Respir Physiol Neurobiol

140

89

97

35. ZhouH

MonackDM

KayagakiN

WertzI

YinJ

2005

Yersinia virulence factor YopJ acts as a deubiquitinase to inhibit NF-kappa B activation.

J Exp Med

202

1327

1332

36. LimJH

HaU

SakaiA

WooCH

KweonSM

2008

Streptococcus pneumoniae synergizes with nontypeable Haemophilus influenzae to induce inflammation via upregulating TLR2.

BMC Immunol

9

40

37. LimJH

JonoH

KogaT

WooCH

IshinagaH

2007

Tumor suppressor CYLD acts as a negative regulator for non-typeable Haemophilus influenza-induced inflammation in the middle ear and lung of mice.

PLoS One

2

e1032

38. SakaiA

KogaT

LimJH

JonoH

HaradaK

2007

The bacterium, nontypeable Haemophilus influenzae, enhances host antiviral response by inducing Toll-like receptor 7 expression: evidence for negative regulation of host anti-viral response by CYLD.

FEBS J

274

3655

3668

39. JonoH

LimJH

ChenLF

XuH

TrompoukiE

2004

NF-kappaB is essential for induction of CYLD, the negative regulator of NF-kappaB: evidence for a novel inducible autoregulatory feedback pathway.

J Biol Chem

279

36171

36174

40. BahlCD

MorisseauC

BombergerJM

StantonBA

HammockBD

2010

Crystal structure of the cystic fibrosis transmembrane conductance regulator inhibitory factor Cif reveals novel active-site features of an epoxide hydrolase virulence factor.

J Bacteriol

192

1785

1795

41. BahlCD

MacEachranDP

O'TooleGA

MaddenDR

2010

Purification, crystallization and preliminary X-ray diffraction analysis of Cif, a virulence factor secreted by Pseudomonas aeruginosa.

Acta Crystallogr Sect F Struct Biol Cryst Commun

66

26

28

42. VerhoefJ

1991

Host-pathogen relationships in respiratory tract infections.

Clin Ther

13

172

180

43. ZhangP

SummerWR

BagbyGJ

NelsonS

2000

Innate immunity and pulmonary host defense.

Immunol Rev

173

39

51

44. BebökZ

VenglarikCJ

PánczélZ

JillingT

KirkKL

1998

Activation of DeltaF508 CFTR in an epithelial monolayer.

Am J Physiol Cell Physiol

275

C599

C607

45. SchliekerC

KorbelGA

KattenhornLM

PloeghHL

2005

A deubiquitinating activity is conserved in the large tegument protein of the herpesviridae.

J Virol

79

15582

15585

46. ButterworthMB

EdingerRS

OvaaH

BurgD

JohnsonJP

2007

The deubiquitinating enzyme UCH-L3 regulates the apical membrane recycling of the epithelial sodium channel.

J Biol Chem

282

37885

37893

47. BiemesderferD

MentoneSA

MoosekerM

HassonT

2002

Expression of myosin VI within the early endocytic pathway in adult and developing proximal tubules.

Am J Physiol Renal Physiol

282

F785

794

48. UrbeS

SachseM

RowPE

PreisingerC

BarrFA

2003

The UIM domain of Hrs couples receptor sorting to vesicle formation.

J Cell Sci

116

4169

4179

49. Swiatecka-UrbanA

DuhaimeM

CoutermarshB

KarlsonKH

CollawnJ

2002

PDZ domain interaction controls the endocytic recycling of the cystic fibrosis transmembrane conductance regulator.

J Biol Chem

277

40099

40105

50. HuCD

GrinbergAV

KerppolaTK

2005

Visualization of protein interactions in living cells using bimolecular fluorescence complementation (BiFC) analysis.

Curr Protoc Protein Sci Chapter

19

Unit 19 10

51. HuCD

ChinenovY

KerppolaTK

2002

Visualization of interactions among bZIP and Rel family proteins in living cells using bimolecular fluorescence complementation.

Mol Cell

9

789

798

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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PLOS Pathogens


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