A Effector with Enhanced Inhibitory
Activity on the NF-κB Pathway Activates the NLRP3/ASC/Caspase-1 Inflammasome
in Macrophages
A type III secretion system (T3SS) in pathogenic Yersinia
species functions to translocate Yop effectors, which modulate cytokine
production and regulate cell death in macrophages. Distinct pathways of
T3SS-dependent cell death and caspase-1 activation occur in
Yersinia-infected macrophages. One pathway of cell death
and caspase-1 activation in macrophages requires the effector YopJ. YopJ is an
acetyltransferase that inactivates MAPK kinases and IKKβ to cause
TLR4-dependent apoptosis in naïve macrophages. A YopJ isoform in Y.
pestis KIM (YopJKIM) has two amino acid substitutions,
F177L and K206E, not present in YopJ proteins of Y.
pseudotuberculosis and Y. pestis CO92. As compared
to other YopJ isoforms, YopJKIM causes increased apoptosis, caspase-1
activation, and secretion of IL-1β in Yersinia-infected
macrophages. The molecular basis for increased apoptosis and activation of
caspase-1 by YopJKIM in Yersinia-infected
macrophages was studied. Site directed mutagenesis showed that the F177L and
K206E substitutions in YopJKIM were important for enhanced apoptosis,
caspase-1 activation, and IL-1β secretion. As compared to
YopJCO92, YopJKIM displayed an enhanced capacity to
inhibit phosphorylation of IκB-α in macrophages and to bind IKKβ in
vitro. YopJKIM also showed a moderately increased ability to inhibit
phosphorylation of MAPKs. Increased caspase-1 cleavage and IL-1β secretion
occurred in IKKβ-deficient macrophages infected with Y.
pestis expressing YopJCO92, confirming that the
NF-κB pathway can negatively regulate inflammasome activation.
K+ efflux, NLRP3 and ASC were important for secretion of
IL-1β in response to Y. pestis KIM infection as shown using
macrophages lacking inflammasome components or by the addition of exogenous KCl.
These data show that caspase-1 is activated in naïve macrophages in
response to infection with a pathogen that inhibits IKKβ and MAPK kinases
and induces TLR4-dependent apoptosis. This pro-inflammatory form of apoptosis
may represent an early innate immune response to highly virulent pathogens such
as Y. pestis KIM that have evolved an enhanced ability to
inhibit host signaling pathways.
Vyšlo v časopise:
A Effector with Enhanced Inhibitory
Activity on the NF-κB Pathway Activates the NLRP3/ASC/Caspase-1 Inflammasome
in Macrophages. PLoS Pathog 7(4): e32767. doi:10.1371/journal.ppat.1002026
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002026
Souhrn
A type III secretion system (T3SS) in pathogenic Yersinia
species functions to translocate Yop effectors, which modulate cytokine
production and regulate cell death in macrophages. Distinct pathways of
T3SS-dependent cell death and caspase-1 activation occur in
Yersinia-infected macrophages. One pathway of cell death
and caspase-1 activation in macrophages requires the effector YopJ. YopJ is an
acetyltransferase that inactivates MAPK kinases and IKKβ to cause
TLR4-dependent apoptosis in naïve macrophages. A YopJ isoform in Y.
pestis KIM (YopJKIM) has two amino acid substitutions,
F177L and K206E, not present in YopJ proteins of Y.
pseudotuberculosis and Y. pestis CO92. As compared
to other YopJ isoforms, YopJKIM causes increased apoptosis, caspase-1
activation, and secretion of IL-1β in Yersinia-infected
macrophages. The molecular basis for increased apoptosis and activation of
caspase-1 by YopJKIM in Yersinia-infected
macrophages was studied. Site directed mutagenesis showed that the F177L and
K206E substitutions in YopJKIM were important for enhanced apoptosis,
caspase-1 activation, and IL-1β secretion. As compared to
YopJCO92, YopJKIM displayed an enhanced capacity to
inhibit phosphorylation of IκB-α in macrophages and to bind IKKβ in
vitro. YopJKIM also showed a moderately increased ability to inhibit
phosphorylation of MAPKs. Increased caspase-1 cleavage and IL-1β secretion
occurred in IKKβ-deficient macrophages infected with Y.
pestis expressing YopJCO92, confirming that the
NF-κB pathway can negatively regulate inflammasome activation.
K+ efflux, NLRP3 and ASC were important for secretion of
IL-1β in response to Y. pestis KIM infection as shown using
macrophages lacking inflammasome components or by the addition of exogenous KCl.
These data show that caspase-1 is activated in naïve macrophages in
response to infection with a pathogen that inhibits IKKβ and MAPK kinases
and induces TLR4-dependent apoptosis. This pro-inflammatory form of apoptosis
may represent an early innate immune response to highly virulent pathogens such
as Y. pestis KIM that have evolved an enhanced ability to
inhibit host signaling pathways.
Zdroje
1. GalanJEWolf-WatzH
2006
Protein delivery into eukaryotic cells by type III secretion
machines.
Nature
444
567
573
2. CornelisGR
2006
The type III secretion injectisome.
Nat Rev Microbiol
4
811
825
3. NavarreWWZychlinskyA
2000
Pathogen-induced apoptosis of macrophages: a common end for
different pathogenic strategies.
Cell Microbiol
2
265
273
4. FinkSLCooksonBT
2005
Apoptosis, pyroptosis, and necrosis: mechanistic description of
dead and dying eukaryotic cells.
Infect Immun
73
1907
1916
5. BergsbakenTFinkSLCooksonBT
2009
Pyroptosis: host cell death and inflammation.
Nat Rev Microbiol
7
99
109
6. BrodskyIEPalmNWSadanandSRyndakMBSutterwalaFS
2010
A Yersinia effector protein promotes virulence by preventing
inflammasome recognition of the type III secretion system.
Cell Host Microbe
7
376
387
7. GretenFRArkanMCBollrathJHsuLCGoodeJ
2007
NF-kappaB is a negative regulator of IL-1beta secretion as
revealed by genetic and pharmacological inhibition of
IKKbeta.
Cell
130
918
931
8. LiloSZhengYBliskaJB
2008
Caspase-1 activation in macrophages infected with Yersinia pestis
KIM requires the type III secretion system effector YopJ.
Infect Immun
76
3911
3923
9. MartinonFTschoppJ
2007
Inflammatory caspases and inflammasomes: master switches of
inflammation.
Cell Death Differ
14
10
22
10. LamkanfiMKannegantiTDFranchiLNunezG
2007
Caspase-1 inflammasomes in infection and
inflammation.
J Leukoc Biol
82
220
225
11. MariathasanSMonackDM
2007
Inflammasome adaptors and sensors: intracellular regulators of
infection and inflammation.
Nat Rev Immunol
7
31
40
12. MartinonFMayorATschoppJ
2009
The inflammasomes: guardians of the body.
Annu Rev Immunol
27
229
265
13. MiaoEALeafIATreutingPMMaoDPDorsM
2010
Caspase-1-induced pyroptosis is an innate immune effector
mechanism against intracellular bacteria.
Nat Immunol
11
1136
1142
14. KannegantiTDLamkanfiMNunezG
2007
Intracellular NOD-like receptors in host defense and
disease.
Immunity
27
549
559
15. SunYHRolanHGTsolisRM
2007
Injection of flagellin into the host cell cytosol by Salmonella
enterica serotype Typhimurium.
J Biol Chem
282
33897
33901
16. MiaoEAAlpuche-ArandaCMDorsMClarkAEBaderMW
2006
Cytoplasmic flagellin activates caspase-1 and secretion of
interleukin 1beta via Ipaf.
Nat Immunol
7
569
575
17. LightfieldKLPerssonJBrubakerSWWitteCEvon MoltkeJ
2008
Critical function for Naip5 in inflammasome activation by a
conserved carboxy-terminal domain of flagellin.
Nat Immunol
9
1171
1178
18. VanceREIsbergRRPortnoyDA
2009
Patterns of pathogenesis: discrimination of pathogenic and
nonpathogenic microbes by the innate immune system.
Cell Host Microbe
6
10
21
19. BauernfeindFGHorvathGStutzAAlnemriESMacDonaldK
2009
Cutting edge: NF-kappaB activating pattern recognition and
cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3
expression.
J Immunol
183
787
791
20. ViboudGIBliskaJB
2005
Yersinia outer proteins: role in modulation of
host cell signaling responses and pathogenesis.
Annu Rev Microbiol
59
69
89
21. MonackDMMecsasJBouleyDFalkowS
1998
Yersinia-induced apoptosis in vivo aids in the
establishment of a systemic infection of mice.
J Exp Med
188
2127
2137
22. ZhangYBliskaJB
2005
Role of macrophage apoptosis in the pathogenesis of
Yersinia.
Curr Top Microbiol Immunol
289
151
173
23. ZhangYTingATMarcuKBBliskaJB
2005
Inhibition of MAPK and NF-kappa B pathways is necessary for rapid
apoptosis in macrophages infected with
Yersinia.
J Immunol
174
7939
7949
24. RuckdeschelKPfaffingerGHaaseRSingAWeighardtH
2004
Signaling of apoptosis through TLRs critically involves toll/IL-1
receptor domain-containing adapter inducing IFN-beta, but not MyD88, in
bacteria-infected murine macrophages.
J Immunol
173
3320
3328
25. ZhangYBliskaJB
2003
Role of Toll-like receptor signaling in the apoptotic response of
macrophages to Yersinia infection.
Infect Immun
71
1513
1519
26. OrthK
2002
Function of the Yersinia effector
YopJ.
Curr Opin Microbiol
5
38
43
27. NeishAS
2004
Bacterial inhibition of eukaryotic pro-inflammatory
pathways.
Immunol Res
29
175
186
28. FehrDCasanovaCLivermanABlazkovaHOrthK
2006
AopP, a type III effector protein of Aeromonas salmonicida,
inhibits the NF-kappaB signalling pathway.
Microbiology
152
2809
2818
29. OrthKXuZMudgettMBBaoZQPalmerLE
2000
Disruption of signaling by Yersinia effector
YopJ, a ubiquitin-like protein protease.
Science
290
1594
1597
30. ZhouHMonackDMKayagakiNWertzIYinJ
2005
Yersinia virulence factor YopJ acts as a deubiquitinase to
inhibit NF-kappa B activation.
J Exp Med
202
1327
1332
31. SweetCRConlonJGolenbockDTGoguenJSilvermanN
2007
YopJ targets TRAF proteins to inhibit TLR-mediated NF-kappaB,
MAPK and IRF3 signal transduction.
Cell Microbiol
9
2700
2715
32. MukherjeeSKeitanyGLiYWangYBallHL
2006
Yersinia YopJ acetylates and inhibits kinase activation by
blocking phosphorylation.
Science
312
1211
1214
33. MittalRPeak-ChewSYMcMahonHT
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. MittalRPeak-ChewSYSadeRSVallisYMcMahonHT
2010
The acetyltransferase activity of the bacterial toxin YopJ of
Yersinia is activated by eukaryotic host cell inositol
hexakisphosphate.
J Biol Chem
285
19927
19934
35. BrodskyIEMedzhitovR
2008
Reduced secretion of YopJ by Yersinia limits in vivo cell death
but enhances bacterial virulence.
PLoS Pathog
4
e1000067
36. TrulzschKSporlederTIgweEIRussmannHHeesemannJ
2004
Contribution of the major secreted yops of Yersinia
enterocolitica O:8 to pathogenicity in the mouse infection
model.
Infect Immun
72
5227
5234
37. ShinHCornelisGR
2007
Type III secretion translocation pores of Yersinia enterocolitica
trigger maturation and release of pro-inflammatory IL-1beta.
Cell Microbiol
9
2893
2902
38. BergsbakenTCooksonBT
2007
Macrophage Activation Redirects
Yersinia-Infected Host Cell Death from Apoptosis to
Caspase-1-Dependent Pyroptosis.
PLoS Pathog
3
e161
39. SchottePDeneckerGVan Den BroekeAVandenabeelePCornelisGR
2004
Targeting Rac1 by the Yersinia effector protein
YopE inhibits caspase-1-mediated maturation and release of
interleukin-1beta.
J Biol Chem
279
25134
25142
40. RuckdeschelKRichterKMannelOHeesemannJ
2001
Arginine-143 of Yersinia enterocolitica YopP
crucially determines isotype-related NF-kappaB suppression and apoptosis
induction in macrophages.
Infect Immun
69
7652
7662
41. ZaubermanACohenSMamroudEFlashnerYTidharA
2006
Interaction of Yersinia pestis with macrophages:
limitations in YopJ-dependent apoptosis.
Infect Immun
74
3239
3250
42. SodeindeOASampleAKBrubakerRRGoguenJD
1988
Plasminogen activator/coagulase gene in Yersinia
pestis is responsible for degredation of plasmid-encoded outer
membrane proteins.
Infect Immun
56
2749
2752
43. GarciaJTFerracciFJacksonMWJosephSSPattisI
2006
Measurement of effector protein injection by type III and type IV
secretion systems by using a 13-residue phosphorylatable glycogen synthase
kinase tag.
Infect Immun
74
5645
5657
44. HaaseRKirschningCJSingASchrottnerPFukaseK
2003
A dominant role of Toll-like receptor 4 in the signaling of
apoptosis in bacteria-faced macrophages.
J Immunol
171
4294
4303
45. HaoYHWangYBurdetteDMukherjeeSKeitanyG
2008
Structural requirements for Yersinia YopJ inhibition of MAP
kinase pathways.
PLoS One
3
e1375
46. CaseCLShinSRoyCR
2009
Asc and Ipaf Inflammasomes direct distinct pathways for caspase-1
activation in response to Legionella pneumophila.
Infect Immun
77
1981
1991
47. SuzukiTFranchiLTomaCAshidaHOgawaM
2007
Differential regulation of caspase-1 activation, pyroptosis, and
autophagy via Ipaf and ASC in Shigella-infected macrophages.
PLoS Pathog
3
e111
48. TingJPWillinghamSBBergstralhDT
2008
NLRs at the intersection of cell death and
immunity.
Nat Rev Immunol
8
372
379
49. KahlenbergJMLundbergKCKertesySBQuYDubyakGR
2005
Potentiation of caspase-1 activation by the P2X7 receptor is
dependent on TLR signals and requires NF-kappaB-driven protein
synthesis.
J Immunol
175
7611
7622
50. ZhangYMurthaJRobertsMASiegelRMBliskaJB
2008
Type III secretion decreases bacterial and host survival
following phagocytosis of Yersinia pseudotuberculosis by
macrophages.
Infect Immun
76
4299
4310
51. FranchiLKannegantiTDDubyakGRNunezG
2007
Differential requirement of P2X7 receptor and intracellular
K+ for caspase-1 activation induced by intracellular and extracellular
bacteria.
J Biol Chem
282
18810
18818
52. ClausenBEBurkhardtCReithWRenkawitzRForsterI
1999
Conditional gene targeting in macrophages and granulocytes using
LysMcre mice.
Transgenic Res
8
265
277
53. PenzoMMolteniRSudaTSamaniegoSRaucciA
2010
Inhibitor of NF-kappa B kinases alpha and beta are both essential
for high mobility group box 1-mediated chemotaxis
[corrected].
J Immunol
184
4497
4509
54. Lara-TejeroMSutterwalaFSOguraYGrantEPBertinJ
2006
Role of the caspase-1 inflammasome in Salmonella typhimurium
pathogenesis.
J Exp Med
203
1407
1412
55. YamamotoMSatoSHemmiHHoshinoKKaishoT
2003
Role of adaptor TRIF in the MyD88-independent toll-like receptor
signaling pathway.
Science
301
640
643
56. CeladaAGrayPWRinderknechtESchreiberRD
1984
Evidence for a gamma-interferon receptor that regulates
macrophage tumoricidal activity.
J Exp Med
160
55
74
57. PujolCBliskaJB
2003
The ability to replicate in macrophages is conserved between
Yersinia pestis and Yersinia pseudotuberculosis.
Infect Immun
71
5892
5899
58. PalmerLEPancettiARGreenbergSBliskaJB
1999
YopJ of Yersinia spp. is sufficient to cause downregulation of
multiple mitogen-activated protein kinases in eukaryotic
cells.
Infect Immun
67
708
716
59. TaoHLiuWSimmonsBNHarrisHKCoxTC
2010
Purifying natively folded proteins from inclusion bodies using
sarkosyl, Triton X-100, and CHAPS.
Biotechniques
48
61
64
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2011 Číslo 4
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- NF-κB Hyper-Activation by HTLV-1 Tax Induces Cellular Senescence, but Can Be Alleviated by the Viral Anti-Sense Protein HBZ
- Bacterial and Host Determinants of MAL Activation upon EPEC Infection: The Roles of Tir, ABRA, and FLRT3
- : Reservoir Hosts and Tracking the Emergence in Humans and Macaques
- On Being the Right Size: The Impact of Population Size and Stochastic Effects on the Evolution of Drug Resistance in Hospitals and the Community