Eis Regulates Autophagy, Inflammation, and Cell Death through Redox-dependent Signaling
The “enhanced intracellular survival” (eis) gene of Mycobacterium tuberculosis (Mtb) is involved in the intracellular survival of M. smegmatis. However, its exact effects on host cell function remain elusive. We herein report that Mtb Eis plays essential roles in modulating macrophage autophagy, inflammatory responses, and cell death via a reactive oxygen species (ROS)-dependent pathway. Macrophages infected with an Mtb eis-deletion mutant H37Rv (Mtb-Δeis) displayed markedly increased accumulation of massive autophagic vacuoles and formation of autophagosomes in vitro and in vivo. Infection of macrophages with Mtb-Δeis increased the production of tumor necrosis factor-α and interleukin-6 over the levels produced by infection with wild-type or complemented strains. Elevated ROS generation in macrophages infected with Mtb-Δeis (for which NADPH oxidase and mitochondria were largely responsible) rendered the cells highly sensitive to autophagy activation and cytokine production. Despite considerable activation of autophagy and proinflammatory responses, macrophages infected with Mtb-Δeis underwent caspase-independent cell death. This cell death was significantly inhibited by blockade of autophagy and c-Jun N-terminal kinase-ROS signaling, suggesting that excessive autophagy and oxidative stress are detrimental to cell survival. Finally, artificial over-expression of Eis or pretreatment with recombinant Eis abrogated production of both ROS and proinflammatory cytokines, which depends on the N-acetyltransferase domain of the Eis protein. Collectively, these data indicate that Mtb Eis suppresses host innate immune defenses by modulating autophagy, inflammation, and cell death in a redox-dependent manner.
Vyšlo v časopise:
Eis Regulates Autophagy, Inflammation, and Cell Death through Redox-dependent Signaling. PLoS Pathog 6(12): e32767. doi:10.1371/journal.ppat.1001230
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1001230
Souhrn
The “enhanced intracellular survival” (eis) gene of Mycobacterium tuberculosis (Mtb) is involved in the intracellular survival of M. smegmatis. However, its exact effects on host cell function remain elusive. We herein report that Mtb Eis plays essential roles in modulating macrophage autophagy, inflammatory responses, and cell death via a reactive oxygen species (ROS)-dependent pathway. Macrophages infected with an Mtb eis-deletion mutant H37Rv (Mtb-Δeis) displayed markedly increased accumulation of massive autophagic vacuoles and formation of autophagosomes in vitro and in vivo. Infection of macrophages with Mtb-Δeis increased the production of tumor necrosis factor-α and interleukin-6 over the levels produced by infection with wild-type or complemented strains. Elevated ROS generation in macrophages infected with Mtb-Δeis (for which NADPH oxidase and mitochondria were largely responsible) rendered the cells highly sensitive to autophagy activation and cytokine production. Despite considerable activation of autophagy and proinflammatory responses, macrophages infected with Mtb-Δeis underwent caspase-independent cell death. This cell death was significantly inhibited by blockade of autophagy and c-Jun N-terminal kinase-ROS signaling, suggesting that excessive autophagy and oxidative stress are detrimental to cell survival. Finally, artificial over-expression of Eis or pretreatment with recombinant Eis abrogated production of both ROS and proinflammatory cytokines, which depends on the N-acetyltransferase domain of the Eis protein. Collectively, these data indicate that Mtb Eis suppresses host innate immune defenses by modulating autophagy, inflammation, and cell death in a redox-dependent manner.
Zdroje
1. PietersJ
2008 Mycobacterium tuberculosis and the macrophage: maintaining a balance. Cell Host Microbe 3 399 407
2. HoubenEN
NguyenL
PietersJ
2006 Interaction of pathogenic mycobacteria with the host immune system. Curr Opin Microbiol 9 76 85
3. DereticV
FrattiRA
1999 Mycobacterium tuberculosis phagosome. Mol Microbiol 31 1603 1609
4. HirayamaY
YoshimuraM
OzekiY
SugawaraI
UdagawaT
2009 Mycobacteria exploit host hyaluronan for efficient extracellular replication. PLoS Pathog 5 e1000643
5. DereticV
LevineB
2009 Autophagy immunity and microbial adaptations. Cell Host Microbe 5 527 549
6. MaiuriMC
ZalckvarE
KimchiA
KroemerG
2007 Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8 741 752
7. GutierrezMG
MasterSS
SinghSB
TaylorGA
ColomboMI
2004 Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119 753 766
8. YukJM
ShinDM
LeeHM
YangCS
JinHS
2009 Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell Host Microbe 6 231 243
9. JagannathC
LindseyDR
DhandayuthapaniS
XuY
HunterRLJr
2009 Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med 15 267 276
10. GalluzziL
VicencioJM
KeppO
TasdemirE
MaiuriMC
2008 To die or not to die: that is the autophagic question. Curr Mol Med 8 78 91
11. MeléndezA
NeufeldTP
2008 The cell biology of autophagy in metazoans: a developing story. Development 135 2347 2360
12. ChenY
GibsonSB
2008 Is mitochondrial generation of reactive oxygen species a trigger for autophagy? Autophagy 4 246 248
13. YukJM
ShinDM
YangCS
KimKH
AnSJ
2009 Role of apoptosis-regulating signal kinase 1 in innate immune responses by Mycobacterium bovis bacillus Calmette-Guérin. Immunol Cell Biol 87 100 107
14. ZhouX
SpangleJM
MüngerK
2009 Expression of a viral oncoprotein in normal human epithelial cells triggers an autophagy-related process: is autophagy an “Achilles' heel” of human cancers? Autophagy 5 578 579
15. WeiJ
DahlJL
MoulderJW
RobertsEA
O'GaoraP
2000 Identification of a Mycobacterium tuberculosis gene that enhances mycobacterial survival in macrophages. J Bacteriol 182 377 384
16. SamuelLP
SongCH
WeiJ
RobertsEA
DahlJL
2007 Expression, production and release of the Eis protein by Mycobacterium tuberculosis during infection of macrophages and its effect on cytokine secretion. Microbiology 153 529 540
17. ZaunbrecherMA
SikesRDJr
MetchockB
ShinnickTM
PoseyJE
2009 Overexpression of the chromosomally encoded aminoglycoside acetyltransferase eis confers kanamycin resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 106 20004 20009
18. WuS
BarnesPF
SamtenB
PangX
RodrigueS
2009 Activation of the eis gene in a W-Beijing strain of Mycobacterium tuberculosis correlates with increased SigA levels and enhanced intracellular growth. Microbiology 155 1272 1281
19. LellaRK
SharmaC
2007 Eis (enhanced intracellular survival) protein of Mycobacterium tuberculosis disturbs the cross regulation of T-cells. J Biol Chem 282 18671 18675
20. KabeyaY
MizushimaN
UenoT
YamamotoA
KirisakoT
2000 LC3 a mammalian homologue of yeast Apg8p is localized in autophagosome membranes after processing. EMBO J 19 5720 5728
21. BlommaartEF
KrauseU
SchellensJP
Vreeling-SindelárováH
MeijerAJ
1997 The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem 243 240 246
22. DereticV
2008 Autophagosome and phagosome. Methods Mol Biol 445 1 10
23. ZakeriZ
MelendezA
LockshinRA
2008 Detection of autophagy in cell death. Methods Enzymol 442 289 306
24. XuY
JagannathC
LiuXD
SharafkhanehA
KolodziejskaKE
EissaNT
2007 Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 27 135 144
25. EskelinenEL
2005 Maturation of autophagic vacuoles in Mammalian cells. Autophagy 1 1 10
26. MizushimaN
YamamotoA
HatanoM
KobayashiY
KabeyaY
2001 Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 152 657 668
27. JoEK
2008 Mycobacterial interaction with innate receptors: TLRs C-type lectins and NLRs. Curr Opin Infect Dis 21 279 286
28. YangCS
ShinDM
KimKH
LeeZW
LeeCH
2009 NADPH oxidase 2 interaction with TLR2 is required for efficient innate immune responses to mycobacteria via cathelicidin expression. J Immunol 182 3696 3705
29. MukhopadhyayP
RajeshM
HaskóG
HawkinsBJ
MadeshM
2007 Simultaneous detection of apoptosis and mitochondrial superoxide production in live cells by flow cytometry and confocal microscopy. Nat Protoc 2 2295 2301
30. HuangJ
CanadienV
LamGY
SteinbergBE
DinauerMC
2009 Activation of antibacterial autophagy by NADPH oxidases. Proc Natl Acad Sci U S A 106 6226 6231
31. Eisenberg-LernerA
BialikS
SimonHU
KimchiA
2009 Life and death partners: apoptosis autophagy and the cross-talk between them. Cell Death Differ 16 966 75
32. PyoJO
NahJ
KimHJ
LeeHJ
HeoJ
2008 Compensatory activation of ERK1/2 in Atg5-deficient mouse embryo fibroblasts suppresses oxidative stress-induced cell death. Autophagy 4 315 321
33. WeiY
PattingreS
SinhaS
BassikM
LevineB
2008 JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 30 678 688
34. YukJM
ShinDM
SongKS
LimK
KimKH
2010 Bacillus calmette-guerin cell wall cytoskeleton enhances colon cancer radiosensitivity through autophagy. Autophagy 6 46 60
35. DahlJL
WeiJ
MoulderJW
LaalS
FriedmanRL
2001 Subcellular localization of the intracellular survival-enhancing Eis protein of Mycobacterium tuberculosis. Infect Immun 69 4295 4302
36. IntemannCD
ThyeT
NiemannS
BrowneEN
AmanuaCM
2009 Autophagy gene variant IRGM -261T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but not by M. africanum strains. PLoS Pathog 5 e1000577
37. JoEK
ParkJK
DockrellHM
2003 Dynamics of cytokine generation in patients with active pulmonary tuberculosis. Curr Opin Infect Dis 16 205 210
38. ShinDM
YukJM
LeeHM
LeeSH
SonJW
2010 Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signaling. Cell Microbiol doi:10.1111/j.1462-5822.2010.01497.x
39. DerrickSC
MorrisSL
2007 The ESAT6 protein of Mycobacterium tuberculosis induces apoptosis of macrophages by activating caspase expression. Cell Microbiol 9 1547 1555
40. DheenadhayalanV
DeloguG
BrennanMJ
2006 Expression of the PE_PGRS 33 protein in Mycobacterium smegmatis triggers necrosis in macrophages and enhanced mycobacterial survival. Microbes Infect 8 262 272
41. VelmuruganK
ChenB
MillerJL
AzogueS
GursesS
2007 Mycobacterium tuberculosis nuoG is a virulence gene that inhibits apoptosis of infected host cells. PLoS Pathog 3 e110
42. MillerJL
VelmuruganK
CowanMJ
BrikenV
2010 The type I NADH dehydrogenase of Mycobacterium tuberculosis counters phagosomal NOX2 activity to inhibit TNF-alpha-mediated host cell apoptosis. PLoS Pathog 6 e1000864
43. TasdemirE
GalluzziL
MaiuriMC
CriolloA
VitaleI
2008 Methods for assessing autophagy and autophagic cell death. Methods Mol Biol 445 29 76
44. KeaneJ
RemoldHG
KornfeldH
2000 Virulent Mycobacterium tuberculosis strains evade apoptosis of infected alveolar macrophages. J Immunol 164 2016 2020
45. KeaneJ
Balcewicz-SablinskaK
RemoldHG
ChuppGL
MeekBB
1997 Infection by Mycobacterium tuberculosis promotes human alveolar macrophage apoptosis. Infect Immun 65 298 304
46. KroemerG
El-DeiryWS
GolsteinP
PeterME
VauxD
2005 Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ 12 1463 1467
47. Di LibertoD
LocatiM
CaccamoN
VecchiA
MeravigliaS
2008 Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in Mycobacterium tuberculosis infection. J Exp Med 205 2075 2084
48. YuL
WanF
DuttaS
WelshS
LiuZ
2006 Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci U S A 103 4952 4957
49. XuY
KimSO
LiY
HanJ
2006 Autophagy contributes to caspase-independent macrophage cell death. J Biol Chem 281 19179 19187
50. Scherz-ShouvalR
ShvetsE
FassE
ShorerH
GilL
2007 Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26 1749 1760
51. WongCH
IskandarKB
YadavSK
HirparaJL
LohT
2010 Simultaneous induction of non-canonical autophagy and apoptosis in cancer cells by ROS-dependent ERK and JNK activation. PLoS One 5 e9996
52. YounceCW
KloattukudyPE
2010 MCP-1 causes cardiomyoblast death via autophagy resulting from ER stress caused by oxidative stress generated by inducing a novel zinc-finger protein, MCPIP. Biochem J 426 43 53
53. LiDD
WangLL
DengR
TangJ
ShenY
2009 The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells. Oncogene 28 886 898
54. BrunkUT
TermanA
2002 The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur J Biochem 269 1996 2002
55. DydaF
KleinDC
HickmanAB
2000 GCN5-related N-acetyltransferases: a structural overview. Annu Rev Biophys Biomol Struct 29 81 103
56. MukherjeeS
KeitanyG
LiY
WangY
BallHL
2006 Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation. Science 312 1211 1214
57. OrthK
PalmerLE
BaoZQ
StewartS
RudolphAE
1999 Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector. Science 285 1920 1923
58. PelicicV
JacksonM
ReyratJM
JacobsJr
GicquelB
GuilhotC
1997 Efficient allelic exchange and transposon mutagenesis in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 94 10955 10960
59. StoverCK
de la CruzVF
FuerstTR
BurleinJE
BensonLA
1991 New use of BCG for recombinant vaccines. Nature 351 456 460
60. SongCH
LeeJS
KimHJ
ParkJK
PaikTH
JoEK
2003 Interleukin-8 is differentially expressed by human-derived monocytic cell line U937 infected with Mycobacterium tuberculosis H37Rv and Mycobacterium marinum. Infect Immun 71 5480 5487
61. YangCS
ShinDM
LeeHM
SonJW
LeeSJ
2008 ASK1-p38 MAPK-p47phox activation is essential for inflammatory responses during tuberculosis via TLR2-ROS signalling. Cell Microbiol 10 741 754
62. FredricksDN
RelmanDA
1999 Paraffin removal from tissue sections for digestion and PCR analysis. Biotechniques 2 198 200
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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