Iron-Responsive miR-485-3p Regulates Cellular Iron Homeostasis by Targeting Ferroportin

English version České info

Ferroportin (FPN) is the only known cellular iron exporter in mammalian cells and plays a critical role in the maintenance of both cellular and systemic iron balance. During iron deprivation, the translation of FPN is repressed by iron regulatory proteins (IRPs), which bind to the 5′ untranslated region (UTR), to reduce iron export and preserve cellular iron. Here, we report a novel iron-responsive mechanism for the post-transcriptional regulation of FPN, mediated by miR-485-3p, which is induced during iron deficiency and represses FPN expression by directly targeting the FPN 3′UTR. The overexpression of miR-485-3p represses FPN expression and leads to increased cellular ferritin levels, consistent with increased cellular iron. Conversely, both inhibition of miR-485-3p activity and mutation of the miR-485-3p target sites on the FPN 3′UTR are able to relieve FPN repression and lead to decreased cellular iron levels. Together, these findings support a model that includes both IRPs and microRNAs as iron-responsive post-transcriptional regulators of FPN. The involvement of microRNA in the iron-responsive regulation of FPN offers additional stability and fine-tuning of iron homeostasis within different cellular contexts. MiR-485-3p-mediated repression of FPN may also offer a novel potential therapeutic mechanism for circumventing hepcidin-resistant mechanisms responsible for some iron overload diseases.

Vyšlo v časopise: Iron-Responsive miR-485-3p Regulates Cellular Iron Homeostasis by Targeting Ferroportin. PLoS Genet 9(4): e32767. doi:10.1371/journal.pgen.1003408
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003408

Souhrn

Zdroje

1. AndrewsNC (2008) Forging a field: the golden age of iron biology. Blood 112: 219–230.

2. WallanderML, LeiboldEA, EisensteinRS (2006) Molecular control of vertebrate iron homeostasis by iron regulatory proteins. Biochimica et Biophysica Acta 1763: 668–689.

3. McKieAT, MarcianiP, RolfsA, BrennanK, WehrK, et al. (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Molecular Cell 5: 299–309.

4. DonovanA, LimaCA, PinkusJL, PinkusGS, ZonLI, et al. (2005) The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metabolism 1: 191–200.

5. AbboudS, HaileDJ (2000) A novel mammalian iron-regulated protein involved in intracellular iron metabolism. Journal of Biological Chemistry 275: 19906–19912.

6. GanzT, NemethE (2011) Hepcidin and disorders of iron metabolism. Annual Review of Medicine 62: 347–360.

7. ZhangDL, SenecalT, GhoshMC, Ollivierre-WilsonH, TuT, et al. (2011) Hepcidin regulates ferroportin expression and intracellular iron homeostasis of erythroblasts. Blood 118: 2868–2877.

8. DelabyC, PilardN, PuyH, Canonne-HergauxF (2008) Sequential regulation of ferroportin expression after erythrophagocytosis in murine macrophages: early mRNA induction by haem, followed by iron-dependent protein expression. The Biochemical journal 411: 123–131.

9. MarroS, ChiabrandoD, MessanaE, StolteJ, TurcoE, et al. (2010) Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter. Haematologica 95: 1261–1268.

10. HentzeMW, MuckenthalerMU, AndrewsNC (2004) Balancing acts: molecular control of mammalian iron metabolism. Cell 117: 285–297.

11. MuckenthalerMU, GalyB, HentzeMW (2008) Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annual Review of Nutrition 28: 197–213.

12. LymboussakiA, PignattiE, MontosiG, GarutiC, HaileDJ, et al. (2003) The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression. Journal of Hepatology 39: 710–715.

13. De DomenicoI, WardDM, LangelierC, VaughnMB, NemethE, et al. (2007) The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Molecular Biology of the Cell 18: 2569–2578.

14. NemethE, TuttleMS, PowelsonJ, VaughnMB, DonovanA, et al. (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306: 2090–2093.

15. FernandesA, PrezaGC, PhungY, De DomenicoI, KaplanJ, et al. (2009) The molecular basis of hepcidin-resistant hereditary hemochromatosis. Blood 114: 437–443.

16. LeePL, BeutlerE (2009) Regulation of hepcidin and iron-overload disease. Annual review of pathology 4: 489–515.

17. DrakesmithH, SchimanskiLM, OrmerodE, Merryweather-ClarkeAT, ViprakasitV, et al. (2005) Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood 106: 1092–1097.

18. ShamRL, PhatakPD, NemethE, GanzT (2009) Hereditary hemochromatosis due to resistance to hepcidin: high hepcidin concentrations in a family with C326S ferroportin mutation. Blood 114: 493–494.

19. BartonJC (2007) Chelation therapy for iron overload. Current gastroenterology reports 9: 74–82.

20. TheilEC, EisensteinRS (2000) Combinatorial mRNA regulation: iron regulatory proteins and iso-iron-responsive elements (Iso-IREs). Journal of Biological Chemistry 275: 40659–40662.

21. StysA, GalyB, StarzynskiRR, SmudaE, DrapierJC, et al. (2011) Iron regulatory protein 1 outcompetes iron regulatory protein 2 in regulating cellular iron homeostasis in response to nitric oxide. The Journal of biological chemistry 286: 22846–22854.

22. TaylorM, QuA, AndersonER, MatsubaraT, MartinA, et al. (2011) Hypoxia-inducible factor-2alpha mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology 140: 2044–2055.

23. AmbrosV (2004) The functions of animal microRNAs. Nature 431: 350–355.

24. BartelDP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281–297.

25. MeisterG (2007) miRNAs get an early start on translational silencing. Cell 131: 25–28.

26. WuL, FanJ, BelascoJG (2006) MicroRNAs direct rapid deadenylation of mRNA. Proceedings of the National Academy of Sciences of the United States of America 103: 4034–4039.

27. LeungAK, SharpPA (2010) MicroRNA functions in stress responses. Molecular cell 40: 205–215.

28. CastoldiM, Vujic SpasicM, AltamuraS, ElmenJ, LindowM, et al. (2011) The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice. The Journal of clinical investigation 121: 1386–1396.

29. KoellerDM, CaseyJL, HentzeMW, GerhardtEM, ChanLN, et al. (1989) A cytosolic protein binds to structural elements within the iron regulatory region of the transferrin receptor mRNA. Proceedings of the National Academy of Sciences of the United States of America 86: 3574–3578.

30. RouaultTA, HentzeMW, CaughmanSW, HarfordJB, KlausnerRD (1988) Binding of a cytosolic protein to the iron-responsive element of human ferritin messenger RNA. Science 241: 1207–1210.

31. BetelD, WilsonM, GabowA, MarksDS, SanderC (2008) The microRNA.org resource: targets and expression. Nucleic Acids Research 36: D149–153.

32. LewisBP, BurgeCB, BartelDP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120: 15–20.

33. ChenCF, HeX, ArslanAD, MoYY, ReinholdWC, et al. (2011) Novel regulation of nuclear factor-YB by miR-485-3p affects the expression of DNA topoisomerase IIalpha and drug responsiveness. Mol Pharmacol 79: 735–741.

34. Muinos-GimenoM, GuidiM, KagerbauerB, Martin-SantosR, NavinesR, et al. (2009) Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders. Hum Mutat 30: 1062–1071.

35. HutvagnerG, SimardMJ, MelloCC, ZamorePD (2004) Sequence-specific inhibition of small RNA function. PLoS Biol 2: e98 doi:10.1371/journal.pbio.0020098.

36. NielsenCB, ShomronN, SandbergR, HornsteinE, KitzmanJ, et al. (2007) Determinants of targeting by endogenous and exogenous microRNAs and siRNAs. RNA 13: 1894–1910.

37. DonovanA, LimaCA, PinkusJL, PinkusGS, ZonLI, et al. (2005) The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 1: 191–200.

38. ZhangDL, HughesRM, Ollivierre-WilsonH, GhoshMC, RouaultTA (2009) A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metabolism 9: 461–473.

39. De DomenicoI, LoE, YangB, KorolnekT, HamzaI, et al. (2011) The role of ubiquitination in hepcidin-independent and hepcidin-dependent degradation of ferroportin. Cell Metabolism 14: 635–646.

40. TongWH, RouaultTA (2006) Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron-sulfur cluster biogenesis and iron homeostasis. Cell Metabolism 3: 199–210.

41. ChanSY, ZhangYY, HemannC, MahoneyCE, ZweierJL, et al. (2009) MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metabolism 10: 273–284.

42. CianettiL, SegnaliniP, CalzolariA, MorsilliO, FelicettiF, et al. (2005) Expression of alternative transcripts of ferroportin-1 during human erythroid differentiation. Haematologica 90: 1595–1606.

43. ZhangDL, HughesRM, Ollivierre-WilsonH, GhoshMC, RouaultTA (2009) A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab 9: 461–473.

44. HafnerM, LandthalerM, BurgerL, KhorshidM, HausserJ, et al. (2010) Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141: 129–141.

45. ChiSW, ZangJB, MeleA, DarnellRB (2009) Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 460: 479–486.

46. KeeneJD (2007) RNA regulons: coordination of post-transcriptional events. Nature Reviews Genetics 8: 533–543.

47. TenenbaumSA, ChristiansenJ, NielsenH (2011) The post-transcriptional operon. Methods in Molecular Biology 703: 237–245.

48. KotaJ, ChivukulaRR, O'DonnellKA, WentzelEA, MontgomeryCL, et al. (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137: 1005–1017.

49. TakeshitaF, PatrawalaL, OsakiM, TakahashiRU, YamamotoY, et al. (2010) Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Molecular therapy : the journal of the American Society of Gene Therapy 18: 181–187.

50. WigginsJF, RuffinoL, KelnarK, OmotolaM, PatrawalaL, et al. (2010) Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer research 70: 5923–5930.

51. ElmenJ, LindowM, SchutzS, LawrenceM, PetriA, et al. (2008) LNA-mediated microRNA silencing in non-human primates. Nature 452: 896–899.

52. LanfordRE, Hildebrandt-EriksenES, PetriA, PerssonR, LindowM, et al. (2010) Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327: 198–201.

53. ChlostaS, FishmanDS, HarringtonL, JohnsonEE, KnutsonMD, et al. (2006) The iron efflux protein ferroportin regulates the intracellular growth of Salmonella enterica. Infection and immunity 74: 3065–3067.

54. NairzM, TheurlI, LudwiczekS, TheurlM, MairSM, et al. (2007) The co-ordinated regulation of iron homeostasis in murine macrophages limits the availability of iron for intracellular Salmonella typhimurium. Cellular microbiology 9: 2126–2140.

55. SangokoyaC, TelenMJ, ChiJT (2010) microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease. Blood 116: 4338–4348.