#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Windpipe Controls Intestinal Homeostasis by Regulating JAK/STAT Pathway via Promoting Receptor Endocytosis and Lysosomal Degradation


Effective tissue homeostasis requires a proper balance between the removal of dead cells and production of new cells. Due to environmental challenges, the Drosophila midgut epithelial cells are damaged from time to time and intestinal stem cells (ISC) can accelerate their proliferative rate to replace the lost midgut epithelium. The JAK/STAT pathway plays essential roles in these progresses. Upon damage, Upd ligands produced by dying enterocytes (ECs) activate JAK/STAT signaling in ISCs to promote their proliferation and differentiation. However, after damage how JAK/STAT signaling is switched from a highly active state to a homeostatic state is not yet fully understood. In this study, we identified the leucine rich repeats (LRR) protein Windpipe (Wdp) as a novel negative feedback regulator of JAK/STAT signaling during intestinal development. Wdp expression was induced by high levels of JAK/STAT signaling in intestines. And loss of Wdp leads to midgut homeostasis loss and increased ISC proliferation. Furthermore, we found Wdp in turn negatively regulates JAK/STAT signaling activity through promoting Domeless receptor endocytosis and lysosomal degradation. In this way, high levels of JAK/STAT signaling is switched off by Wdp, which ensure ISCs return to the homeostatic state after tissue damage.


Vyšlo v časopise: Windpipe Controls Intestinal Homeostasis by Regulating JAK/STAT Pathway via Promoting Receptor Endocytosis and Lysosomal Degradation. PLoS Genet 11(4): e32767. doi:10.1371/journal.pgen.1005180
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005180

Souhrn

Effective tissue homeostasis requires a proper balance between the removal of dead cells and production of new cells. Due to environmental challenges, the Drosophila midgut epithelial cells are damaged from time to time and intestinal stem cells (ISC) can accelerate their proliferative rate to replace the lost midgut epithelium. The JAK/STAT pathway plays essential roles in these progresses. Upon damage, Upd ligands produced by dying enterocytes (ECs) activate JAK/STAT signaling in ISCs to promote their proliferation and differentiation. However, after damage how JAK/STAT signaling is switched from a highly active state to a homeostatic state is not yet fully understood. In this study, we identified the leucine rich repeats (LRR) protein Windpipe (Wdp) as a novel negative feedback regulator of JAK/STAT signaling during intestinal development. Wdp expression was induced by high levels of JAK/STAT signaling in intestines. And loss of Wdp leads to midgut homeostasis loss and increased ISC proliferation. Furthermore, we found Wdp in turn negatively regulates JAK/STAT signaling activity through promoting Domeless receptor endocytosis and lysosomal degradation. In this way, high levels of JAK/STAT signaling is switched off by Wdp, which ensure ISCs return to the homeostatic state after tissue damage.


Zdroje

1. Arbouzova NI, Zeidler MP. JAK/STAT signalling in Drosophila: insights into conserved regulatory and cellular functions. Development. 2006 Jul;133(14):2605–16. 16794031

2. Agaisse H, Perrimon N. The roles of JAK/STAT signaling in Drosophila immune responses. Immunol Rev. 2004 Apr;198:72–82. 15199955

3. Fuller MT, Spradling AC. Male and female Drosophila germline stem cells: two versions of immortality. Science. 2007 Apr 20;316(5823):402–4. 17446390

4. Hou SX, Zheng Z, Chen X, Perrimon N. The Jak/STAT pathway in model organisms: emerging roles in cell movement. Dev Cell. 2002 Dec;3(6):765–78. 12479803

5. Schindler CW. Series introduction. JAK-STAT signaling in human disease. J Clin Invest. 2002 May;109(9):1133–7. 11994400

6. Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity. 2006 Nov;25(5):745–55. 17088085

7. Calo V, Migliavacca M, Bazan V, Macaluso M, Buscemi M, Gebbia N, et al. STAT proteins: from normal control of cellular events to tumorigenesis. J Cell Physiol. 2003 Nov;197(2):157–68. 14502555

8. O'Shea JJ, Gadina M, Schreiber RD. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell. 2002 Apr;109 Suppl:S121–31. 11983158

9. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci. 2004 Mar 15;117(Pt 8):1281–3. 15020666

10. Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol. 2003 Nov;3(11):900–11. 14668806

11. Brown S, Hu N, Hombria JC. Identification of the first invertebrate interleukin JAK/STAT receptor, the Drosophila gene domeless. Curr Biol. 2001 Oct 30;11(21):1700–5. 11696329

12. Chen HW, Chen X, Oh SW, Marinissen MJ, Gutkind JS, Hou SX. mom identifies a receptor for the Drosophila JAK/STAT signal transduction pathway and encodes a protein distantly related to the mammalian cytokine receptor family. Genes Dev. 2002 Feb 1;16(3):388–98. 11825879

13. Binari R, Perrimon N. Stripe-specific regulation of pair-rule genes by hopscotch, a putative Jak family tyrosine kinase in Drosophila. Genes Dev. 1994 Feb 1;8(3):300–12. 8314084

14. Hou XS, Melnick MB, Perrimon N. Marelle acts downstream of the Drosophila HOP/JAK kinase and encodes a protein similar to the mammalian STATs. Cell. 1996 Feb 9;84(3):411–9. 8608595

15. Yan R, Small S, Desplan C, Dearolf CR, Darnell JE Jr. Identification of a Stat gene that functions in Drosophila development. Cell. 1996 Feb 9;84(3):421–30. 8608596

16. Harrison DA, McCoon PE, Binari R, Gilman M, Perrimon N. Drosophila unpaired encodes a secreted protein that activates the JAK signaling pathway. Genes Dev. 1998 Oct 15;12(20):3252–63. 9784499

17. Hombria JC, Brown S, Hader S, Zeidler MP. Characterisation of Upd2, a Drosophila JAK/STAT pathway ligand. Dev Biol. 2005 Dec 15;288(2):420–33. 16277982

18. Agaisse H, Petersen UM, Boutros M, Mathey-Prevot B, Perrimon N. Signaling role of hemocytes in Drosophila JAK/STAT-dependent response to septic injury. Dev Cell. 2003 Sep;5(3):441–50. 12967563

19. Hombria JC, Brown S. The fertile field of Drosophila Jak/STAT signalling. Curr Biol. 2002 Aug 20;12(16):R569–75. 12194841

20. Callus BA, Mathey-Prevot B. SOCS36E, a novel Drosophila SOCS protein, suppresses JAK/STAT and EGF-R signalling in the imaginal wing disc. Oncogene. 2002 Jul 18;21(31):4812–21. 12101419

21. Baeg GH, Zhou R, Perrimon N. Genome-wide RNAi analysis of JAK/STAT signaling components in Drosophila. Genes Dev. 2005 Aug 15;19(16):1861–70. 16055650

22. Muller P, Kuttenkeuler D, Gesellchen V, Zeidler MP, Boutros M. Identification of JAK/STAT signalling components by genome-wide RNA interference. Nature. 2005 Aug 11;436(7052):871–5. 16094372

23. Micchelli CA, Perrimon N. Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature. 2006 Jan 26;439(7075):475–9. 16340959

24. Ohlstein B, Spradling A. The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature. 2006 Jan 26;439(7075):470–4. 16340960

25. Ohlstein B, Spradling A. Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential notch signaling. Science. 2007 Feb 16;315(5814):988–92. 17303754

26. Jiang H, Patel PH, Kohlmaier A, Grenley MO, McEwen DG, Edgar BA. Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell. 2009 Jun 26;137(7):1343–55. doi: 10.1016/j.cell.2009.05.014 19563763

27. Beebe K, Lee WC, Micchelli CA. JAK/STAT signaling coordinates stem cell proliferation and multilineage differentiation in the Drosophila intestinal stem cell lineage. Dev Biol. 2010 Feb 1;338(1):28–37. doi: 10.1016/j.ydbio.2009.10.045 19896937

28. Lin G, Xu N, Xi R. Paracrine unpaired signaling through the JAK/STAT pathway controls self-renewal and lineage differentiation of drosophila intestinal stem cells. J Mol Cell Biol. 2010 Feb;2(1):37–49. doi: 10.1093/jmcb/mjp028 19797317

29. Jiang H, Edgar BA. EGFR signaling regulates the proliferation of Drosophila adult midgut progenitors. Development. 2009 Feb;136(3):483–93. doi: 10.1242/dev.026955 19141677

30. Jiang H, Grenley MO, Bravo MJ, Blumhagen RZ, Edgar BA. EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila. Cell Stem Cell. 2011 Jan 7;8(1):84–95. doi: 10.1016/j.stem.2010.11.026 21167805

31. Biteau B, Jasper H. EGF signaling regulates the proliferation of intestinal stem cells in Drosophila. Development. 2011 Mar;138(6):1045–55. doi: 10.1242/dev.056671 21307097

32. Ren F, Wang B, Yue T, Yun EY, Ip YT, Jiang J. Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways. Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):21064–9. doi: 10.1073/pnas.1012759107 21078993

33. Staley BK, Irvine KD. Warts and Yorkie mediate intestinal regeneration by influencing stem cell proliferation. Curr Biol. 2010 Sep 14;20(17):1580–7. doi: 10.1016/j.cub.2010.07.041 20727758

34. Karpowicz P, Perez J, Perrimon N. The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration. Development. 2010 Dec;137(24):4135–45. doi: 10.1242/dev.060483 21098564

35. Choi NH, Lucchetta E, Ohlstein B. Nonautonomous regulation of Drosophila midgut stem cell proliferation by the insulin-signaling pathway. Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):18702–7. doi: 10.1073/pnas.1109348108 22049341

36. Li H, Qi Y, Jasper H. Dpp signaling determines regional stem cell identity in the regenerating adult Drosophila gastrointestinal tract. Cell Rep. 2013 Jul 11;4(1):10–8. doi: 10.1016/j.celrep.2013.05.040 23810561

37. Li Z, Zhang Y, Han L, Shi L, Lin X. Trachea-derived dpp controls adult midgut homeostasis in Drosophila. Dev Cell. 2013 Jan 28;24(2):133–43. doi: 10.1016/j.devcel.2012.12.010 23369712

38. Tian A, Jiang J. Intestinal epithelium-derived BMP controls stem cell self-renewal in Drosophila adult midgut. Elife. 2014;3:e01857. doi: 10.7554/eLife.01857 24618900

39. Guo Z, Driver I, Ohlstein B. Injury-induced BMP signaling negatively regulates Drosophila midgut homeostasis. J Cell Biol. 2013 Jun 10;201(6):945–61. doi: 10.1083/jcb.201302049 23733344

40. Lin G, Xu N, Xi R. Paracrine Wingless signalling controls self-renewal of Drosophila intestinal stem cells. Nature. 2008 Oct 23;455(7216):1119–23. doi: 10.1038/nature07329 18806781

41. Lee WC, Beebe K, Sudmeier L, Micchelli CA. Adenomatous polyposis coli regulates Drosophila intestinal stem cell proliferation. Development. 2009 Jul;136(13):2255–64. doi: 10.1242/dev.035196 19502486

42. Liu W, Singh SR, Hou SX. JAK-STAT is restrained by Notch to control cell proliferation of the Drosophila intestinal stem cells. J Cell Biochem. 2010 Apr 1;109(5):992–9. doi: 10.1002/jcb.22482 20082318

43. Xu N, Wang SQ, Tan D, Gao Y, Lin G, Xi R. EGFR, Wingless and JAK/STAT signaling cooperatively maintain Drosophila intestinal stem cells. Dev Biol. 2011 Jun 1;354(1):31–43. doi: 10.1016/j.ydbio.2011.03.018 21440535

44. Buchon N, Broderick NA, Poidevin M, Pradervand S, Lemaitre B. Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation. Cell Host Microbe. 2009 Feb 19;5(2):200–11. doi: 10.1016/j.chom.2009.01.003 19218090

45. Cronin SJ, Nehme NT, Limmer S, Liegeois S, Pospisilik JA, Schramek D, et al. Genome-wide RNAi screen identifies genes involved in intestinal pathogenic bacterial infection. Science. 2009 Jul 17;325(5938):340–3. doi: 10.1126/science.1173164 19520911

46. Buchon N, Broderick NA, Chakrabarti S, Lemaitre B. Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila. Genes Dev. 2009 Oct 1;23(19):2333–44. doi: 10.1101/gad.1827009 19797770

47. Huff JL, Kingsley KL, Miller JM, Hoshizaki DK. Drosophila windpipe codes for a leucine-rich repeat protein expressed in the developing trachea. Mech Dev. 2002 Feb;111(1–2):173–6. 11804793

48. Flaherty MS, Salis P, Evans CJ, Ekas LA, Marouf A, Zavadil J, et al. chinmo is a functional effector of the JAK/STAT pathway that regulates eye development, tumor formation, and stem cell self-renewal in Drosophila. Dev Cell. 2010 Apr 20;18(4):556–68. doi: 10.1016/j.devcel.2010.02.006 20412771

49. Karsten P, Hader S, Zeidler MP. Cloning and expression of Drosophila SOCS36E and its potential regulation by the JAK/STAT pathway. Mech Dev. 2002 Sep;117(1–2):343–6. 12204286

50. Leatherman JL, Dinardo S. Zfh-1 controls somatic stem cell self-renewal in the Drosophila testis and nonautonomously influences germline stem cell self-renewal. Cell Stem Cell. 2008 Jul 3;3(1):44–54. doi: 10.1016/j.stem.2008.05.001 18593558

51. Ghiglione C, Devergne O, Georgenthum E, Carballes F, Medioni C, Cerezo D, et al. The Drosophila cytokine receptor Domeless controls border cell migration and epithelial polarization during oogenesis. Development. 2002 Dec;129(23):5437–47. 12403714

52. Ichiba M, Nakajima K, Yamanaka Y, Kiuchi N, Hirano T. Autoregulation of the Stat3 gene through cooperation with a cAMP-responsive element-binding protein. J Biol Chem. 1998 Mar 13;273(11):6132–8. 9497331

53. Wawersik M, Milutinovich A, Casper AL, Matunis E, Williams B, Van Doren M. Somatic control of germline sexual development is mediated by the JAK/STAT pathway. Nature. 2005 Jul 28;436(7050):563–7. 16049490

54. Amcheslavsky A, Jiang J, Ip YT. Tissue damage-induced intestinal stem cell division in Drosophila. Cell Stem Cell. 2009 Jan 9;4(1):49–61. doi: 10.1016/j.stem.2008.10.016 19128792

55. Lee T, Luo L. Mosaic analysis with a repressible cell marker (MARCM) for Drosophila neural development. Trends Neurosci. 2001 May;24(5):251–4. 11311363

56. Wang YH, Huang ML. Organogenesis and tumorigenesis: insight from the JAK/STAT pathway in the Drosophila eye. Dev Dyn. 2010 Oct;239(10):2522–33. doi: 10.1002/dvdy.22394 20737505

57. Singh SR, Chen X, Hou SX. JAK/STAT signaling regulates tissue outgrowth and male germline stem cell fate in Drosophila. Cell Res. 2005 Jan;15(1):1–5. 15686618

58. Bach EA, Ekas LA, Ayala-Camargo A, Flaherty MS, Lee H, Perrimon N, et al. GFP reporters detect the activation of the Drosophila JAK/STAT pathway in vivo. Gene Expr Patterns. 2007 Jan;7(3):323–31. 17008134

59. Vidal OM, Stec W, Bausek N, Smythe E, Zeidler MP. Negative regulation of Drosophila JAK-STAT signalling by endocytic trafficking. J Cell Sci. 2010 Oct 15;123(Pt 20):3457–66. doi: 10.1242/jcs.066902 20841381

60. Sotillos S, Diaz-Meco MT, Moscat J, Castelli-Gair Hombria J. Polarized subcellular localization of Jak/STAT components is required for efficient signaling. Curr Biol. 2008 Apr 22;18(8):624–9. doi: 10.1016/j.cub.2008.03.055 18424141

61. Devergne O, Ghiglione C, Noselli S. The endocytic control of JAK/STAT signalling in Drosophila. J Cell Sci. 2007 Oct 1;120(Pt 19):3457–64. 17855388

62. Stec W, Vidal O, Zeidler MP. Drosophila SOCS36E negatively regulates JAK/STAT pathway signaling via two separable mechanisms. Mol Biol Cell. 2013 Sep;24(18):3000–9. doi: 10.1091/mbc.E13-05-0275 23885117

63. Buchon N, Broderick NA, Kuraishi T, Lemaitre B. Drosophila EGFR pathway coordinates stem cell proliferation and gut remodeling following infection. BMC Biol. 2010;8:152. doi: 10.1186/1741-7007-8-152 21176204

64. Biteau B, Hochmuth CE, Jasper H. JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell. 2008 Oct 9;3(4):442–55. doi: 10.1016/j.stem.2008.07.024 18940735

65. Shaw RL, Kohlmaier A, Polesello C, Veelken C, Edgar BA, Tapon N. The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration. Development. 2010 Dec;137(24):4147–58. doi: 10.1242/dev.052506 21068063

66. Vodovar N, Vinals M, Liehl P, Basset A, Degrouard J, Spellman P, et al. Drosophila host defense after oral infection by an entomopathogenic Pseudomonas species. Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11414–9. 16061818

67. Gilbert MM, Beam CK, Robinson BS, Moberg KH. Genetic interactions between the Drosophila tumor suppressor gene ept and the stat92E transcription factor. PLoS One. 2009;4(9):e7083. doi: 10.1371/journal.pone.0007083 19787055

68. Thomas C, Strutt D. Rabaptin-5 and Rabex-5 are neoplastic tumour suppressor genes that interact to modulate Rab5 dynamics in Drosophila melanogaster. Dev Biol. 2014 Jan 1;385(1):107–21. doi: 10.1016/j.ydbio.2013.09.029 24104056

69. Ni JQ, Zhou R, Czech B, Liu LP, Holderbaum L, Yang-Zhou D, et al. A genome-scale shRNA resource for transgenic RNAi in Drosophila. Nat Methods. 2011 May;8(5):405–7. doi: 10.1038/nmeth.1592 21460824

70. Belenkaya TY, Wu Y, Tang X, Zhou B, Cheng L, Sharma YV, et al. The retromer complex influences Wnt secretion by recycling wntless from endosomes to the trans-Golgi network. Dev Cell. 2008 Jan;14(1):120–31. 18160348

71. Han C, Belenkaya TY, Khodoun M, Tauchi M, Lin X. Distinct and collaborative roles of Drosophila EXT family proteins in morphogen signalling and gradient formation. Development. 2004 Apr;131(7):1563–75. 14998928

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2015 Číslo 4
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#