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Integration of UPR and Oxidative Stress Signaling in the Control of Intestinal Stem Cell Proliferation


Loss of proper protein homeostasis (proteostasis) as well as increased production of reactive oxygen species (ROS) is a hallmark of aging. In complex metazoans, these processes can result in proliferative diseases and cancers. The protein folding capacity of the endoplasmic reticulum (ER) is monitored and maintained by the unfolded protein response of the ER (UPRER). In this study, we identify a coordinated role of UPRER and oxidative stress signaling in regulating the proliferation of intestinal stem cells (ISCs). We find that the ER-stress responsive transcription factor Xbp1 and the ER-associated degradation pathway component Hrd1 are sufficient and required cell autonomously in ISCs to limit their proliferative activity. This function is dependent on the activities of the stress sensor JNK and the redox-responsive transcription factor CncC, which we have previously identified as regulators of ISC proliferation. We further show here that promoting ER homeostasis in aging ISCs is sufficient to limit age-associated epithelial dysplasia. Our results establish the integration of UPRER and oxidative stress signaling as a central mechanism promoting regenerative homeostasis in the intestinal epithelium.


Vyšlo v časopise: Integration of UPR and Oxidative Stress Signaling in the Control of Intestinal Stem Cell Proliferation. PLoS Genet 10(8): e32767. doi:10.1371/journal.pgen.1004568
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004568

Souhrn

Loss of proper protein homeostasis (proteostasis) as well as increased production of reactive oxygen species (ROS) is a hallmark of aging. In complex metazoans, these processes can result in proliferative diseases and cancers. The protein folding capacity of the endoplasmic reticulum (ER) is monitored and maintained by the unfolded protein response of the ER (UPRER). In this study, we identify a coordinated role of UPRER and oxidative stress signaling in regulating the proliferation of intestinal stem cells (ISCs). We find that the ER-stress responsive transcription factor Xbp1 and the ER-associated degradation pathway component Hrd1 are sufficient and required cell autonomously in ISCs to limit their proliferative activity. This function is dependent on the activities of the stress sensor JNK and the redox-responsive transcription factor CncC, which we have previously identified as regulators of ISC proliferation. We further show here that promoting ER homeostasis in aging ISCs is sufficient to limit age-associated epithelial dysplasia. Our results establish the integration of UPRER and oxidative stress signaling as a central mechanism promoting regenerative homeostasis in the intestinal epithelium.


Zdroje

1. KaserA, LeeA-H, FrankeA, GlickmanJN, ZeissigS, et al. (2008) XBP1 Links ER Stress to Intestinal Inflammation and Confers Genetic Risk for Human Inflammatory Bowel Disease. Cell 134: 743–756 doi:10.1016/j.cell.2008.07.021

2. NiederreiterL, FritzTMJ, AdolphTE, KrismerAM, OffnerFA, et al. (2013) ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells. Journal of Experimental Medicine 210: 2041–2056 doi:10.1038/nature07589

3. GlimcherLH (2009) XBP1: the last two decades. Annals of the Rheumatic Diseases 69: i67–i71 doi:10.1136/ard.2009.119388

4. GarrettWS, GordonJI, GlimcherLH (2010) Homeostasis and inflammation in the intestine. Cell 140: 859–870 doi:10.1016/j.cell.2010.01.023

5. KaserA, ZeissigS, BlumbergRS (2010) Inflammatory bowel disease. Annu Rev Immunol 28: 573–621 doi:10.1146/annurev-immunol-030409-101225

6. KaserA, FlakMB, TomczakMF, BlumbergRS (2011) The unfolded protein response and its role in intestinal homeostasis and inflammation. Experimental Cell Research 317: 2772–2779 doi:10.1016/j.yexcr.2011.07.008

7. AdolphTE, TomczakMF, NiederreiterL, KoH-J, BöckJ, et al. (2013) Paneth cells as a site of origin for intestinal inflammation. Nature 503: 272–276 doi:10.1038/nature12599

8. WalterP, RonD (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334: 1081–1086 doi:10.1126/science.1209038

9. SchröderM, KaufmanRJ (2005) THE MAMMALIAN UNFOLDED PROTEIN RESPONSE. Annu Rev Biochem 74: 739–789 doi:10.1146/annurev.biochem.73.011303.074134

10. TraversKJ, PatilCK, WodickaL, LockhartDJ, WeissmanJS, et al. (2000) Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101: 249–258.

11. RyooHD, StellerH (2007) Unfolded protein response in Drosophila: why another model can make it fly. Cell Cycle 6: 830–835.

12. SmithMH, PloeghHL, WeissmanJS (2011) Road to ruin: targeting proteins for degradation in the endoplasmic reticulum. Science 334: 1086–1090 doi:10.1126/science.1209235

13. FrandAR, KaiserCA (1999) Ero1p oxidizes protein disulfide isomerase in a pathway for disulfide bond formation in the endoplasmic reticulum. Mol Cell 4: 469–477.

14. KimS, SiderisDP, SevierCS, KaiserCA (2012) Balanced Ero1 activation and inactivation establishes ER redox homeostasis. The Journal of Cell Biology 196: 713–725 doi:10.1083/jcb.201110090

15. GrossE, SevierCS, HeldmanN, VituE, BentzurM, et al. (2006) Generating disulfides enzymatically: reaction products and electron acceptors of the endoplasmic reticulum thiol oxidase Ero1p. Proc Natl Acad Sci USA 103: 299–304 doi:10.1073/pnas.0506448103

16. HeijmansJ, van Lidth de JeudeJF, KooB-K, RosekransSL, WielengaMCB, et al. (2013) ER Stress Causes Rapid Loss of Intestinal Epithelial Stemness through Activation of the Unfolded Protein Response. Cell reports 3: 1128–1139 doi:10.1016/j.celrep.2013.02.031

17. Owusu-AnsahE, BanerjeeU (2009) Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461: 537–541 doi:10.1038/nature08313

18. NobleM, SmithJ, PowerJ, Mayer-ProschelM (2003) Redox state as a central modulator of precursor cell function. Annals of the New York Academy of Sciences 991: 251–271.

19. HochmuthCE, BiteauB, BohmannD, JasperH (2011) Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. Cell Stem Cell 8: 188–199 doi:10.1016/j.stem.2010.12.006

20. TothovaZ, GillilandDG (2007) FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system. Cell Stem Cell 1: 140–152.

21. LuoB, LeeAS (2013) The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene 32: 805–818 doi:10.1038/onc.2012.130

22. MicchelliCA, PerrimonN (2006) Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature 439: 475–479 doi:10.1038/nature04371

23. OhlsteinB, SpradlingA (2006) The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature 439: 470–474 doi:10.1038/nature04333

24. BiteauB, HochmuthCE, JasperH (2011) Maintaining tissue homeostasis: dynamic control of somatic stem cell activity. Cell Stem Cell 9: 402–411 doi:10.1016/j.stem.2011.10.004

25. BuchonN, BroderickNA, LemaitreB (2013) Gut homeostasis in a microbial world: insights from Drosophila melanogaster. Nature reviews Microbiology 11: 615–626 doi:10.1038/nrmicro3074

26. CullinanSB, DiehlJA (2006) Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. The international journal of biochemistry & cell biology 38: 317–332.

27. Glover-CutterKM, LinS, BlackwellTK (2013) Integration of the Unfolded Protein and Oxidative Stress Responses through SKN-1/Nrf. PLoS Genet 9: e1003701 doi:10.1371/journal.pgen.1003701

28. BiteauB, HochmuthCE, JasperH (2008) JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell 3: 442–455 doi:10.1016/j.stem.2008.07.024

29. ChoiNH, KimJG, YangDJ, KimYS, YooMA (2008) Age-related changes in Drosophila midgut are associated with PVF2, a PDGF/VEGF-like growth factor. Aging Cell 7: 318–334 doi:10.1111/j.1474-9726.2008.00380.x

30. ReraM, ClarkRI, WalkerDW (2012) Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila. Proceedings of the National Academy of Sciences 109: 21528–21533 doi:10.1073/pnas.1215849110

31. BiteauB, KarpacJ, SupoyoS, DeGennaroM, LehmannR, et al. (2010) Lifespan extension by preserving proliferative homeostasis in Drosophila. PLoS Genet 6: e1001159.

32. GuoL, KarpacJ, TranSL, JasperH (2014) PGRP-SC2 Promotes Gut Immune Homeostasis to Limit Commensal Dysbiosis and Extend Lifespan. Cell 156: 109–122 doi:10.1016/j.cell.2013.12.018

33. RyooHD, LiJ, KangM-J (2013) Drosophila XBP1 expression reporter marks cells under endoplasmic reticulum stress and with high protein secretory load. PLoS ONE 8: e75774 doi:10.1371/journal.pone.0075774

34. SoneM, ZengX, LareseJ, RyooHD (2013) A modified UPR stress sensing system reveals a novel tissue distribution of IRE1/XBP1 activity during normal Drosophila development. Cell Stress Chaperones 18: 307–319 doi:10.1007/s12192-012-0383-x

35. JiangH, PatelPH, KohlmaierA, GrenleyMO, McEwenDG, et al. (2009) Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell 137: 1343–1355 doi:10.1016/j.cell.2009.05.014

36. OhlsteinB, SpradlingA (2007) Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential notch signaling. Science 315: 988–992 doi:10.1126/science.1136606

37. Casas-TintoS, ZhangY, Sanchez-GarciaJ, Gomez-VelazquezM, Rincon-LimasDE, et al. (2011) The ER stress factor XBP1s prevents amyloid-beta neurotoxicity. Human Molecular Genetics 20: 2144–2160 doi:10.1093/hmg/ddr100

38. BordalloJ, PlemperRK, FingerA, WolfDH (1998) Der3p/Hrd1p is required for endoplasmic reticulum-associated degradation of misfolded lumenal and integral membrane proteins. Molecular biology of the cell 9: 209–222.

39. ZengX, ChauhanC, HouSX (2010) Characterization of midgut stem cell- and enteroblast-specific Gal4 lines in drosophila. Genesis 48: 607–611 doi:10.1002/dvg.20661

40. LuoL (2007) Fly MARCM and mouse MADM: genetic methods of labeling and manipulating single neurons. Brain Res Rev 55: 220–227 doi:10.1016/j.brainresrev.2007.01.012

41. ChoiG, ParkSH, HwangS, HanSY, HongYK, et al. (n.d.) Interference in xbp1 gene expression induces defective cell differentiation and sensory organ development in Drosophila. Genes & Genomics 32: 233–238 doi:10.1007/s13258-010-0002-0

42. KangM-J, RyooHD (2009) Suppression of retinal degeneration in Drosophila by stimulation of ER-associated degradation. Proceedings of the National Academy of Sciences 106: 17043–17048 doi:10.1073/pnas.0905566106

43. DornerAJ, BoleDG, KaufmanRJ (1987) The relationship of N-linked glycosylation and heavy chain-binding protein association with the secretion of glycoproteins. The Journal of cell biology 105: 2665–2674.

44. BiteauB, KarpacJ, HwangboD, JasperH (2010) Regulation of Drosophila lifespan by JNK signaling. Exp Gerontol 46: 349–354 doi:10.1016/j.exger.2010.11.003

45. KapuriaS, KarpacJ, BiteauB, HwangboD, JasperH (2012) Notch-mediated suppression of TSC2 expression regulates cell differentiation in the Drosophila intestinal stem cell lineage. PLoS Genet 8: e1003045.

46. AmcheslavskyA, JiangJ, IpYT (2009) Tissue damage-induced intestinal stem cell division in Drosophila. Cell Stem Cell 4: 49–61 doi:10.1016/j.stem.2008.10.016

47. HardingHP, ZhangY, ZengH, NovoaI, LuPD, et al. (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11: 619–633.

48. SevierCS, KaiserCA (2008) Ero1 and redox homeostasis in the endoplasmic reticulum. Biochimica et biophysica acta 1783: 549–556 doi:10.1016/j.bbamcr.2007.12.011

49. TuBP, WeissmanJS (2004) Oxidative protein folding in eukaryotes: mechanisms and consequences. The Journal of cell biology 164: 341–346 doi:10.1083/jcb.200311055

50. DeGennaroM, HurdTR, SiekhausDE, BiteauB, JasperH, et al. (2011) Peroxiredoxin stabilization of DE-cadherin promotes primordial germ cell adhesion. Dev Cell 20: 233–243 doi:10.1016/j.devcel.2010.12.007

51. SykiotisGP, BohmannD (2008) Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila. Dev Cell 14: 76–85 doi:10.1016/j.devcel.2007.12.002

52. BiteauB, JasperH (2011) EGF signaling regulates the proliferation of intestinal stem cells in Drosophila. Development 138: 1045–1055 doi:10.1242/dev.056671

53. Henis-KorenblitS, ZhangP, HansenM, McCormickM, LeeSJ, et al. (2010) Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity. Proceedings of the National Academy of Sciences 107: 9730–9735 doi:10.1073/pnas.1002575107

54. TaylorRC, DillinA (2013) XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. Cell 153: 1435–1447 doi:10.1016/j.cell.2013.05.042

55. KourtisN, TavernarakisN (2011) Cellular stress response pathways and ageing: intricate molecular relationships. EMBO J 30: 2520–2531 doi:10.1038/emboj.2011.162

56. TaylorRC, DillinA (2011) Aging as an event of proteostasis collapse. Cold Spring Harbor perspectives in biology 3 doi:10.1101/cshperspect.a004440

57. GrootjansJ, HodinCM, de HaanJ-J, DerikxJPM, RouschopKMA, et al. (2011) Level of activation of the unfolded protein response correlates with Paneth cell apoptosis in human small intestine exposed to ischemia/reperfusion. Gastroenterology 140: 529–539.e3 doi:10.1053/j.gastro.2010.10.040

58. RichardsonCE, KooistraT, KimDH (2010) An essential role for XBP-1 in host protection against immune activation in C. elegans. Nature 463: 1092–1095 doi:10.1038/nature08762

59. LeeT, LuoL (2001) Mosaic analysis with a repressible cell marker (MARCM) for Drosophila neural development. Trends Neurosci 24: 251–254.

60. RyooHD, DomingosPM, KangM-J, StellerH (2006) Unfolded protein response in a Drosophila model for retinal degeneration. EMBO J 26: 242–252 doi:10.1038/sj.emboj.7601477

61. LinG, XuN, XiR (2008) Paracrine Wingless signalling controls self-renewal of Drosophila intestinal stem cells. Nature 455: 1119–1123 doi:10.1038/nature07329

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