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Persistent ER Stress Induces the Spliced Leader RNA Silencing Pathway (SLS), Leading to Programmed Cell Death in


Trypanosomes are parasites that cycle between the insect host (procyclic form) and mammalian host (bloodstream form). These parasites lack conventional transcription regulation, including factors that induce the unfolded protein response (UPR). However, they possess a stress response mechanism, the spliced leader RNA silencing (SLS) pathway. SLS elicits shut-off of spliced leader RNA (SL RNA) transcription by perturbing the binding of the transcription factor tSNAP42 to its cognate promoter, thus eliminating trans-splicing of all mRNAs. Induction of endoplasmic reticulum (ER) stress in procyclic trypanosomes elicits changes in the transcriptome similar to those induced by conventional UPR found in other eukaryotes. The mechanism of up-regulation under ER stress is dependent on differential stabilization of mRNAs. The transcriptome changes are accompanied by ER dilation and elevation in the ER chaperone, BiP. Prolonged ER stress induces SLS pathway. RNAi silencing of SEC63, a factor that participates in protein translocation across the ER membrane, or SEC61, the translocation channel, also induces SLS. Silencing of these genes or prolonged ER stress led to programmed cell death (PCD), evident by exposure of phosphatidyl serine, DNA laddering, increase in reactive oxygen species (ROS) production, increase in cytoplasmic Ca2+, and decrease in mitochondrial membrane potential, as well as typical morphological changes observed by transmission electron microscopy (TEM). ER stress response is also induced in the bloodstream form and if the stress persists it leads to SLS. We propose that prolonged ER stress induces SLS, which serves as a unique death pathway, replacing the conventional caspase-mediated PCD observed in higher eukaryotes.


Vyšlo v časopise: Persistent ER Stress Induces the Spliced Leader RNA Silencing Pathway (SLS), Leading to Programmed Cell Death in. PLoS Pathog 6(1): e32767. doi:10.1371/journal.ppat.1000731
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000731

Souhrn

Trypanosomes are parasites that cycle between the insect host (procyclic form) and mammalian host (bloodstream form). These parasites lack conventional transcription regulation, including factors that induce the unfolded protein response (UPR). However, they possess a stress response mechanism, the spliced leader RNA silencing (SLS) pathway. SLS elicits shut-off of spliced leader RNA (SL RNA) transcription by perturbing the binding of the transcription factor tSNAP42 to its cognate promoter, thus eliminating trans-splicing of all mRNAs. Induction of endoplasmic reticulum (ER) stress in procyclic trypanosomes elicits changes in the transcriptome similar to those induced by conventional UPR found in other eukaryotes. The mechanism of up-regulation under ER stress is dependent on differential stabilization of mRNAs. The transcriptome changes are accompanied by ER dilation and elevation in the ER chaperone, BiP. Prolonged ER stress induces SLS pathway. RNAi silencing of SEC63, a factor that participates in protein translocation across the ER membrane, or SEC61, the translocation channel, also induces SLS. Silencing of these genes or prolonged ER stress led to programmed cell death (PCD), evident by exposure of phosphatidyl serine, DNA laddering, increase in reactive oxygen species (ROS) production, increase in cytoplasmic Ca2+, and decrease in mitochondrial membrane potential, as well as typical morphological changes observed by transmission electron microscopy (TEM). ER stress response is also induced in the bloodstream form and if the stress persists it leads to SLS. We propose that prolonged ER stress induces SLS, which serves as a unique death pathway, replacing the conventional caspase-mediated PCD observed in higher eukaryotes.


Zdroje

1. MalhotraJD

KaufmanRJ

2007 The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18 716 731

2. VembarSS

BrodskyJL

2008 One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 9 944 957

3. TraversKJ

PatilCK

WodickaL

LockhartDJ

WeissmanJS

2000 Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101 249 258

4. RonD

WalterP

2007 Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8 519 529

5. BernalesS

PapaFR

WalterP

2006 Intracellular signaling by the unfolded protein response. Annu Rev Cell Dev Biol 22 487 508

6. KawaharaT

YanagiH

YuraT

MoriK

1997 Endoplasmic reticulum stress-induced mRNA splicing permits synthesis of transcription factor Hac1p/Ern4p that activates the unfolded protein response. Mol Biol Cell 8 1845 1862

7. CoxJS

ChapmanRE

WalterP

1997 The unfolded protein response coordinates the production of endoplasmic reticulum protein and endoplasmic reticulum membrane. Mol Biol Cell 8 1805 1814

8. CalfonM

ZengH

UranoF

TillJH

HubbardSR

2002 IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415 92 96

9. YoshidaH

MatsuiT

HosokawaN

KaufmanRJ

NagataK

2003 A time-dependent phase shift in the mammalian unfolded protein response. Dev Cell 4 265 271

10. HazeK

YoshidaH

YanagiH

YuraT

MoriK

1999 Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10 3787 3799

11. LeeK

TirasophonW

ShenX

MichalakM

PrywesR

2002 IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev 16 452 466

12. YeJ

RawsonRB

KomuroR

ChenX

DaveUP

2000 ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 6 1355 1364

13. MorishimaN

NakanishiK

TakenouchiH

ShibataT

YasuhikoY

2002 An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. J Biol Chem 277 34287 34294

14. RaoRV

Castro-ObregonS

FrankowskiH

SchulerM

StokaV

2002 Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsic pathway. J Biol Chem 277 21836 21842

15. LiangXH

HaritanA

UlielS

MichaeliS

2003 trans and cis splicing in Trypanosomatids: mechanism, factors, and regulation. Eukaryot Cell 2 830 840

16. AgabianN

1990 Trans splicing of nuclear pre-mRNAs. Cell 61 1157 1160

17. FeaginJE

1990 RNA editing in kinetoplastid mitochondria. J Biol Chem 265 19373 19376

18. StuartKD

SchnauferA

ErnstNL

PanigrahiAK

2005 Complex management: RNA editing in trypanosomes. Trends Biochem Sci 30 97 105

19. ClaytonC

ShapiraM

2007 Post-transcriptional regulation of gene expression in trypanosomes and leishmanias. Mol Biochem Parasitol 156 93 101

20. DasA

ZhangQ

PalencharJB

ChatterjeeB

CrossGA

2005 Trypanosomal TBP functions with the multisubunit transcription factor tSNAP to direct spliced-leader RNA gene expression. Mol Cell Biol 25 7314 7322

21. SchimanskiB

NguyenTN

GunzlA

2005 Characterization of a multisubunit transcription factor complex essential for spliced-leader RNA gene transcription in Trypanosoma brucei. Mol Cell Biol 25 7303 7313

22. CampbellDA

ThomasS

SturmNR

2003 Transcription in kinetoplastid protozoa: why be normal? Microbes Infect 5 1231 1240

23. LustigY

SheinerL

VagimaY

GoldshmidtH

DasA

2007 Spliced-leader RNA silencing: a novel stress-induced mechanism in Trypanosoma brucei. EMBO Rep 8 408 413

24. KoumandouVL

NatesanSK

SergeenkoT

FieldMC

2008 The trypanosome transcriptome is remodelled during differentiation but displays limited responsiveness within life stages. BMC Genomics 9 298

25. DuszenkoM

FigarellaK

MacleodET

WelburnSC

2006 Death of a trypanosome: a selfish altruism. Trends in Parasitology 22 536 542

26. WelburnSC

MacleodE

FigarellaK

DuzenskoM

2006 Programmed cell death in African trypanosomes. Parasitology 132 Suppl S7 S18

27. GonzalezIJ

DespondsC

SchaffC

MottramJC

FaselN

2007 Leishmania major metacaspase can replace yeast metacaspase in programmed cell death and has arginine-specific cysteine peptidase activity. Int J Parasitol 37 161 172

28. HelmsMJ

AmbitA

AppletonP

TetleyL

CoombsGH

2006 Bloodstream form Trypanosoma brucei depend upon multiple metacaspases associated with RAB11-positive endosomes. J Cell Sci 119 1105 1117

29. LeeN

GannavaramS

SelvapandiyanA

DebrabantA

2007 Characterization of metacaspases with trypsin-like activity and their putative role in programmed cell death in the protozoan parasite Leishmania. Eukaryot Cell 6 1745 1757

30. AbrahamMC

ShahamS

2004 Death without caspases, caspases without death. Trends Cell Biol 14 184 193

31. BesteiroS

WilliamsRA

MorrisonLS

CoombsGH

MottramJC

2006 Endosome sorting and autophagy are essential for differentiation and virulence of Leishmania major. J Biol Chem 281 11384 11396

32. WilliamsRA

WoodsKL

JulianoL

MottramJC

CoombsGH

2009 Characterization of unusual families of ATG8-like proteins and ATG12 in the protozoan parasite Leishmania major. Autophagy 5 159 172

33. ShenX

EllisRE

SakakiK

KaufmanRJ

2005 Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans. PLoS Genet 1 e37 doi:10.1371/journal.pgen.0010037

34. HollienJ

WeissmanJS

2006 Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313 104 107

35. MurrayJI

WhitfieldML

TrinkleinND

MyersRM

BrownPO

2004 Diverse and specific gene expression responses to stresses in cultured human cells. Mol Biol Cell 15 2361 2374

36. ColasanteC

RoblesA

LiCH

SchwedeA

BenzC

2007 Regulated expression of glycosomal phosphoglycerate kinase in Trypanosoma brucei. Mol Biochem Parasitol 151 193 204

37. EllgaardL

MolinariM

HeleniusA

1999 Setting the standards: quality control in the secretory pathway. Science 286 1882 1888

38. RutkowskiDT

ArnoldSM

MillerCN

WuJ

LiJ

2006 Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol 4 e374 doi:10.1371/journal.pbio.0040374

39. LeeAS

2005 The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods 35 373 381

40. DatemaR

LezicaRP

RobbinsPW

SchwarzRT

1981 Deoxyglucose inhibition of protein glycosylation: effects of nucleotide deoxysugars on the formation of glucosylated lipid intermediates. Arch Biochem Biophys 206 65 71

41. BackSH

SchroderM

LeeK

ZhangK

KaufmanRJ

2005 ER stress signaling by regulated splicing: IRE1/HAC1/XBP1. Methods 35 395 416

42. BernalesS

McDonaldKL

WalterP

2006 Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol 4 e423 doi:10.1371/journal.pbio.0040423

43. BommiasamyH

BackSH

FagoneP

LeeK

MeshinchiS

2009 ATF6alpha induces XBP1-independent expansion of the endoplasmic reticulum. J Cell Sci 122 1626 1636

44. TkaczID

LustigY

SternMZ

BitonM

Salmon-DivonM

2007 Identification of novel snRNA-specific Sm proteins that bind selectively to U2 and U4 snRNAs in Trypanosoma brucei. RNA 13 30 43

45. HuryA

GoldshmidtH

TkaczID

MichaeliS

2009 Trypanosome spliced-leader-associated RNA (SLA1) localization and implications for spliced-leader RNA biogenesis. Eukaryot Cell 8 56 68

46. GoldshmidtH

SheinerL

ButikoferP

RoditiI

UlielS

2008 Role of protein translocation pathways across the endoplasmic reticulum in Trypanosoma brucei. J Biol Chem 283 32085 32098

47. DarzynkiewiczZ

BednerE

SmolewskiP

2001 Flow cytometry in analysis of cell cycle and apoptosis. Semin Hematol 38 179 193

48. van EngelandM

NielandLJ

RamaekersFC

SchutteB

ReutelingspergerCP

1998 Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31 1 9

49. MandelboimM

BarthS

BitonM

LiangXH

MichaeliS

2003 Silencing of Sm proteins in Trypanosoma brucei by RNA interference captured a novel cytoplasmic intermediate in spliced leader RNA biogenesis. J Biol Chem 278 51469 51478

50. SternMZ

GuptaSK

Salmon-DivonM

HahamT

BardaO

2009 Multiple roles for polypyrimidine tract binding (PTB) proteins in trypanosome RNA metabolism. RNA 15 648 665

51. PintonP

GiorgiC

SivieroR

ZecchiniE

RizzutoR

2008 Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene 27 6407 6418

52. LuHG

ZhongL

ChangKP

DocampoR

1997 Intracellular Ca2+ pool content and signaling and expression of a calcium pump are linked to virulence in Leishmania mexicana amazonesis amastigotes. J Biol Chem 272 9464 9473

53. BenaimG

Lopez-EstranoC

DocampoR

MorenoSN

1993 A calmodulin-stimulated Ca2+ pump in plasma-membrane vesicles from Trypanosoma brucei; selective inhibition by pentamidine. Biochem J 296 (Pt3) 759 763

54. NolanDP

ReverlardP

PaysE

1994 Overexpression and characterization of a gene for a Ca(2+)-ATPase of the endoplasmic reticulum in Trypanosoma brucei. J Biol Chem 269 26045 26051

55. MorenoSN

DocampoR

VercesiAE

1992 Calcium homeostasis in procyclic and bloodstream forms of Trypanosoma brucei. Lack of inositol 1,4,5-trisphosphate-sensitive Ca2+ release. J Biol Chem 267 6020 6026

56. DocampoR

MorenoSN

1999 Acidocalcisome: A novel Ca2+ storage compartment in trypanosomatids and apicomplexan parasites. Parasitol Today 15 443 448

57. DocampoR

ScottDA

VercesiAE

MorenoSN

1995 Intracellular Ca2+ storage in acidocalcisomes of Trypanosoma cruzi. Biochem J 310 ( Pt3) 1005 1012

58. RidgleyEL

XiongZH

RubenL

1999 Reactive oxygen species activate a Ca2+-dependent cell death pathway in the unicellular organism Trypanosoma brucei brucei. Biochem J 340 ( Pt1) 33 40

59. GeeKR

BrownKA

ChenWN

Bishop-StewartJ

GrayD

2000 Chemical and physiological characterization of fluo-4 Ca(2+)-indicator dyes. Cell Calcium 27 97 106

60. FlorykD

HoustekJ

1999 Tetramethyl rhodamine methyl ester (TMRM) is suitable for cytofluorometric measurements of mitochondrial membrane potential in cells treated with digitonin. Biosci Rep 19 27 34

61. BassDA

ParceJW

DechateletLR

SzejdaP

SeedsMC

1983 Flow cytometric studies of oxidative product formation by neutrophils: a graded response to membrane stimulation. J Immunol 130 1910 1917

62. LiuX

KimCN

YangJ

JemmersonR

WangX

1996 Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86 147 157

63. GannavaramS

VedvyasC

DebrabantA

2008 Conservation of the pro-apoptotic nuclease activity of endonuclease G in unicellular trypanosomatid parasites. J Cell Sci 121 99 109

64. LevineB

2005 Eating oneself and uninvited guests: autophagy-related pathways in cellular defense. Cell 120 159 162

65. YorimitsuT

NairU

YangZ

KlionskyDJ

2006 Endoplasmic reticulum stress triggers autophagy. Journal of Biological Chemistry 281 30299 30304

66. GozuacikD

KimchiA

2007 Autophagy and cell death. Curr Top Dev Biol 78 217 245

67. IzquierdoL

AtrihA

RodriguesJA

JonesDC

FergusonMA

2009 Trypanosoma brucei UDP-glucose:glycoprotein glucosyltransferase has unusual substrate specificity and protects the parasite from stress. Eukaryot Cell 8 230 240

68. ConteI

LabriolaC

CazzuloJJ

DocampoR

ParodiAJ

2003 The interplay between folding-facilitating mechanisms in Trypanosoma cruzi endoplasmic reticulum. Mol Biol Cell 14 3529 3540

69. KramerS

QueirozR

EllisL

WebbH

HoheiselJD

2008 Heat shock causes a decrease in polysomes and the appearance of stress granules in trypanosomes independently of eIF2{alpha} phosphorylation at Thr169. J Cell Sci 121 3002 3014

70. MoraesMC

JesusTC

HashimotoNN

DeyM

SchwartzKJ

2007 Novel membrane-bound eIF2alpha kinase in the flagellar pocket of Trypanosoma brucei. Eukaryot Cell 6 1979 1991

71. FigarellaK

RawerM

UzcateguiNL

KubataBK

LauberK

2005 Prostaglandin D2 induces programmed cell death in Trypanosoma brucei bloodstream form. Cell Death Differ 12 335 346

72. VassellaE

ReunerB

YutzyB

BoshartM

1997 Differentiation of African trypanosomes is controlled by a density sensing mechanism which signals cell cycle arrest via the cAMP pathway. J Cell Sci 110 ( Pt21) 2661 2671

73. FigarellaK

UzcateguiNL

BeckA

SchoenfeldC

KubataBK

2006 Prostaglandin-induced programmed cell death in Trypanosoma brucei involves oxidative stress. Cell Death Differ 13 1802 1814

74. DocampoR

MorenoSN

2001 The acidocalcisome. Mol Biochem Parasitol 114 151 159

75. MorenoSN

DocampoR

2009 The role of acidocalcisomes in parasitic protists. J Eukaryot Microbiol 56 208 213

76. ShimizuS

NaritaM

TsujimotoY

1999 Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399 483 487

77. JeongSY

SeolDW

2008 The role of mitochondria in apoptosis. BMB Rep 41 11 22

78. LiLY

LuoX

WangX

2001 Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412 95 99

79. FeissnerRF

SkalskaJ

GaumWE

SheuSS

2009 Crosstalk signaling between mitochondrial Ca2+ and ROS. Front Biosci 14 1197 1218

80. RaoRV

EllerbyHM

BredesenDE

2004 Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ 11 372 380

81. LinJH

LiH

ZhangY

RonD

WalterP

2009 Divergent effects of PERK and IRE1 signaling on cell viability. PLoS ONE 4 e4170 doi:10.1371/journal.pone.0004170

82. WangZ

MorrisJC

DrewME

EnglundPT

2000 Inhibition of Trypanosoma brucei gene expression by RNA interference using an integratable vector with opposing T7 promoters. J Biol Chem 275 40174 40179

83. BrunR

Schonenberger

1979 Cultivation and in vitro cloning or procyclic culture forms of Trypanosoma brucei in a semi-defined medium. Short communication. Acta Trop 36 289 292

84. HaileS

EstevezAM

ClaytonC

2003 A role for the exosome in the in vivo degradation of unstable mRNAs. RNA 9 1491 1501

85. HirumiH

HirumiK

1989 Continuous cultivation of Trypanosoma brucei blood stream forms in a medium containing a low concentration of serum protein without feeder cell layers. J Parasitol 75 985 989

86. LiuL

LiangXH

UlielS

UngerR

UlluE

2002 RNA interference of signal peptide-binding protein SRP54 elicits deleterious effects and protein sorting defects in trypanosomes. Journal of Biological Chemistry 277 47348 47357

87. CominiMA

GuerreroSA

HaileS

MengeU

LunsdorfH

2004 Validation of Trypanosoma brucei trypanothione synthetase as drug target. Free Radic Biol Med 36 1289 1302

88. KellyS

ReedJ

KramerS

EllisL

WebbH

2007 Functional genomics in Trypanosoma brucei: a collection of vectors for the expression of tagged proteins from endogenous and ectopic gene loci. Mol Biochem Parasitol 154 103 109

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