The Proprotein Convertase Encoded by () Is Required in Corpora Cardiaca Endocrine Cells Producing the Glucose Regulatory Hormone AKH

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Peptide hormones are potent signaling molecules that coordinate animal physiology, behavior, and development. A key step in activation of these peptide signals is their proteolytic processing from propeptide precursors by a family of proteases, the subtilisin-like proprotein convertases (PCs). Here, we report the functional dissection of amontillado (amon), which encodes the Drosophila homolog of the mammalian PC2 protein, using cell-type specific inactivation and rescue experiments, and we show that amon is required in the islet-like adipokinetic hormone (AKH)–producing cells that regulate sugar homeostasis. In Drosophila, AKH acts analogously to vertebrate glucagon to increase circulating sugar levels from energy stores, while insulin-like peptides (DILPs) act to decrease sugar levels. amon mutant larvae have significantly reduced hemolymph sugar levels, and thus phenocopy larvae where the AKH–producing cells in the corpora cardiaca have been ablated. Reduction of amon expression in these cells via cell-specific RNA inactivation also results in larvae with reduced sugar levels while expression of amon in AKH cells in an amon mutant background rescues hypoglycemia. Hypoglycemia in larvae resulting from amon RNA inactivation in the AKH cells can be rescued by global expression of the akh gene. Finally, mass spectrometric profiling shows that the production of mature AKH is inhibited in amon mutants. Our data indicate that amon function in the AKH cells is necessary to maintain normal sugar homeostasis, that amon functions upstream of akh, and that loss of mature AKH is correlated with loss of amon activity. These observations indicate that the AKH propeptide is a proteolytic target of the amon proprotein convertase and provide evidence for a conserved role of PC2 in processing metabolic peptide hormones.

Vyšlo v časopise: The Proprotein Convertase Encoded by () Is Required in Corpora Cardiaca Endocrine Cells Producing the Glucose Regulatory Hormone AKH. PLoS Genet 6(5): e32767. doi:10.1371/journal.pgen.1000967
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000967

Souhrn

Zdroje

1. SossinWS

FisherJM

SchellerRH

1989 Cellular and molecular biology of neuropeptide processing and packaging. Neuron 2 1407 1417

2. StrandFL

1999 New vistas for melanocortins. Finally, an explanation for their pleiotropic functions. Ann N Y Acad Sci 897 1 16

3. ZhouA

WebbG

ZhuXR

SteinerDF

1999 Proteolytic processing in the secretory pathway. Journal of Biological Chemistry 274 20745 20748

4. FurutaM

YanoH

ZhouA

RouilleY

HolstJJ

1997 Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proceedings of the National Academy of Sciences of the United States of America 94 6646 6651

5. NillniEA

2007 Regulation of prohormone convertases in hypothalamic neurons: implications for prothyrotropin-releasing hormone and proopiomelanocortin. Endocrinology 148 4191 4200

6. RouilleY

DuguaySJ

LundK

FurutaM

GongQ

1995 Proteolytic processing mechanisms in the biosynthesis of neuroendocrine peptides: the subtilisin-like proprotein convertases. Front Neuroendocrinol 16 322 361

7. HelwigM

KhorooshiRM

TupsA

BarrettP

ArcherZA

2006 PC1/3 and PC2 gene expression and post-translational endoproteolytic pro-opiomelanocortin processing is regulated by photoperiod in the seasonal Siberian hamster (Phodopus sungorus). J Neuroendocrinol 18 413 425

8. SanchezVC

GoldsteinJ

StuartRC

HovanesianV

HuoL

2004 Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone. J Clin Invest 114 357 369

9. HookVYH

AzaryanAV

HwangSR

TezapsidisN

1994 Proteases and the emerging role of protease inhibitors in prohormone processing Faseb Journal 8 1269 1278

10. OsterwalderT

KuhnenA

LeisersonWM

KimYS

KeshishianH

2004 Drosophila serpin 4 functions as a neuroserpin-like inhibitor of subtilisin-like proprotein convertases. Journal of Neuroscience 24 5482 5491

11. ReichhartJM

2005 Tip of another iceberg: Drosophila serpins. Trends Cell Biol 15 659 665

12. IkeyaT

GalicM

BelawatP

NairzK

HafenE

2002 Nutrient-dependent expression of insulin-like peptides from neuroendocrine cells in the CNS contributes to growth regulation in Drosophila. Current Biology 12 1293 1300

13. KimSK

RulifsonEJ

2004 Conserved mechanisms of glucose sensing and regulation by Drosophila corpora cardiaca cells. Nature 431 316 320

14. ParkJH

SchroederAJ

Helfrich-ForsterC

JacksonFR

EwerJ

2003 Targeted ablation of CCAP neuropeptide-containing neurons of Drosophila causes specific defects in execution and circadian timing of ecdysis behavior. Development 130 2645 2656

15. RulifsonEJ

KimSK

NusseR

2002 Ablation of insulin-producing neurons in flies: Growth and diabetic phenotypes. Science 296 1118 1120

16. EwerJ

2005 Behavioral actions of neuropeptides in invertebrates: insights from Drosophila. Horm Behav 48 418 429

17. NasselDR

2002 Neuropeptides in the nervous system of Drosophila and other insects: multiple roles as neuromodulators and neurohormones. Progress in Neurobiology 68 1 84

18. TaghertPH

VeenstraJA

2003 Drosophila neuropeptide signaling. Advances in Genetics, Vol 49 San Diego Academic Press Inc 1 65

19. ZitnanD

KimYJ

ZitnanovaI

RollerL

AdamsME

2007 Complex steroid-peptide-receptor cascade controls insect ecdysis. Gen Comp Endocrinol 153 88 96

20. DavisMM

O'KeefeSL

PrimroseDA

HodgettsRB

2007 A neuropeptide hormone cascade controls the precise onset of post-eclosion cuticular tanning in Drosophila melanogaster. Development 134 4395 4404

21. HenrichVC

RybczynskiR

GilbertLI

1999 Peptide hormones, steroid hormones, and puffs: mechanisms and models in insect development. Vitam Horm 55 73 125

22. McBrayerZ

OnoH

ShimellM

ParvyJP

BecksteadRB

2007 Prothoracicotropic hormone regulates developmental timing and body size in Drosophila. Dev Cell 13 857 871

23. NijhoutHF

1994 Genes on the wing. Science 265 44 45

24. SiekhausDE

FullerRS

1999 A role for amontillado, the Drosophila homolog of the neuropeptide precursor processing protease PC2, in triggering hatching behavior. Journal of Neuroscience 19 6942 6954

25. RoebroekAJ

CreemersJW

PauliIG

BogaertT

Van de VenWJ

1993 Generation of structural and functional diversity in furin-like proteins in Drosophila melanogaster by alternative splicing of the Dfur1 gene. EMBO J 12 1853 1870

26. RoebroekAJM

AyoubiTAY

CreemersJWM

PauliIGL

VandevenWJM

1995 The dfur2 gene of Drosophila melanogaster - genetic organization, expression during embryogenesis, and pro-protein processing activity of its translational product dfurin2. DNA and Cell Biology 14 223 234

27. RayburnLY

RheaJ

JocoySR

BenderM

2009 The proprotein convertase amontillado (amon) is required during Drosophila pupal development. Dev Biol 333 48 56

28. RayburnLYM

GoodingHC

ChoksiSP

MaloneyD

KiddAR

2003 amontillado, the Drosophila homolog of the prohormone processing protease PC2, is required during embryogenesis and early larval development. Genetics 163 227 237

29. HwangJR

SiekhausDE

FullerRS

TaghertPH

LindbergI

2000 Interaction of Drosophila melanogaster prohormone convertase 2 and 7B2 - Insect cell-specific processing and secretion. Journal of Biological Chemistry 275 17886 17893

30. KodrikD

SochaR

SimekP

ZemekR

GoldsworthyGJ

2000 A new member of the AKH/RPCH family that stimulates locomotory activity in the firebug, Pyrrhocoris apterus (Heteroptera). Insect Biochemistry and Molecular Biology 30 489 498

31. KollischGV

LorenzMW

KellnerR

VerhaertPD

HoffmannKH

2000 Structure elucidation and biological activity of an unusual adipokinetic hormone from corpora cardiaca of the butterfly, Vanessa cardui. European Journal of Biochemistry 267 5502 5508

32. SchafferMH

NoyesBE

SlaughterCA

ThorneGC

GaskellSJ

1990 The fruitfly Drosophila melanogaster contains a novel charged adipokinetic hormone family peptide. Biochemical Journal 269 315 320

33. SiegertKJ

KellnerR

GadeG

2000 A third active AKH is present in the pyrgomorphid grasshoppers Phymateus morbillosus and Dictyophorus spumans. Insect Biochemistry and Molecular Biology 30 1061 1067

34. StoneJV

MordueW

BatleyKE

MorrisHR

1976 Structure of locust adipokinetic hormone, a neurohormone that regulates lipid utilization during flight. Nature 263 207 211

35. Van der HorstDJ

2003 Insect adipokinetic hormones: release and integration of flight energy metabolism. Comparative Biochemistry and Physiology B-Biochemistry & Molecular Biology 136 217 226

36. IsabelG

MartinJR

ChidamiS

VeenstraJA

RosayP

2005 AKH-producing neuroendocrine cell ablation decreases trehalose and induces behavioral changes in Drosophila. American Journal of Physiology-Regulatory Integrative and Comparative Physiology 288 R531 R538

37. LeeGH

ParkJH

2004 Hemolymph sugar homeostasis and starvation-induced hyperactivity affected by genetic manipulations of the adipokinetic hormone-encoding gene in Drosophila melanogaster. Genetics 167 311 323

38. WyattGR

1961 Biochemistry of Insect Hemolymph. Annual Review of Entomology 6 75 &

39. GadeG

2004 Regulation of intermediary metabolism and water balance of insects by neuropeptides. Annual Review of Entomology 49 93 113

40. NoyesBE

KatzFN

SchafferMH

1995 Identification and expression of the Drosophila adipokinetic hormone gene. Molecular and Cellular Endocrinology 109 133 141

41. PredelR

WegenerC

RussellWK

TichySE

RussellDH

2004 Peptidomics of CNS-associated neurohemal systems of adult Drosophila melanogaster: a mass spectrometric survey of peptides from individual flies. J Comp Neurol 474 379 392

42. WegenerC

ReinlT

JanschL

PredelR

2006 Direct mass spectrometric peptide profiling and fragmentation of larval peptide hormone release sites in Drosophila melanogaster reveals tagma-specific peptide expression and differential processing. Journal of Neurochemistry 96 1362 1374

43. RayneRC

O'SheaM

1994 Reconstitution of adipokinetic hormone biosynthesis in-vitro indicates steps in prohormone processing. European Journal of Biochemistry 219 781 789

44. BrogioloW

StockerH

IkeyaT

RintelenF

FernandezR

2001 An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Current Biology 11 213 221

45. KaufmannC

BrownMR

2006 Adipokinetic hormones in the African malaria mosquito, Anopheles gambiae: Identification and expression of genes for two peptides and a putative receptor. Insect Biochemistry and Molecular Biology 36 466 481

46. GobomJ

NordhoffE

2002 Quantitative Analysis of neuropeptides by MALDI-TOF MS.

SilberringJ

EckmanR

Mass spectrometry and hyphenated techniques in neuropeptide research New York Wiley and Sons

47. SzajliE

FeherT

MedzihradszkyKF

2008 Investigating the quantitative nature of MALDI-TOF MS. Mol Cell Proteomics 7 2410 2418

48. FurutaM

ZhouA

WebbG

CarrollR

RavazzolaM

2001 Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice. Journal of Biological Chemistry 276 27197 27202

49. WangS

TulinaN

CarlinDL

RulifsonEJ

2007 The origin of islet-like cells in Drosophila identifies parallels to the vertebrate endocrine axis. Proceedings of the National Academy of Sciences of the United States of America 104 19873 19878

50. GromadaJ

FranklinI

WollheimCB

2007 Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev 28 84 116

51. RouilleY

WestermarkG

MartinSK

SteinerDF

1994 Proglucagon is processed to glucagon by prohormone convertase PC2 in alpha TC1-6 cells. Proc Natl Acad Sci U S A 91 3242 3246

52. PanH

CheFY

PengB

SteinerDF

PintarJE

2006 The role of prohormone convertase-2 in hypothalamic neuropeptide processing: a quantitative neuropeptidomic study. Journal of Neurochemistry 98 1763 1777

53. AllenRG

PengB

PellegrinoMJ

MillerED

GrandyDK

2001 Altered processing of pro-orphanin FQ/nociceptin and pro-opiomelanocortin-derived peptides in the brains of mice expressing defective prohormone convertase 2. Journal of Neuroscience 21 5864 5870

54. JimenezCR

LiKW

DreisewerdK

MansvelderHD

BrussaardAB

1997 Pattern changes of pituitary peptides in rat after salt-loading as detected by means of direct, semiquantitative mass spectrometric profiling. Proc Natl Acad Sci U S A 94 9481 9486

55. JimenezCR

ter MaatA

PienemanA

BurlingameAL

SmitAB

2004 Spatio-temporal dynamics of the egg-laying-inducing peptides during an egg-laying cycle: a semiquantitative matrix-assisted laser desorption/ionization mass spectrometry approach. J Neurochem 89 865 875

56. DiederenJHB

OudejansR

HarthoornLF

Van der HorstDJ

2002 Cell biology of the adipokinetic hormone-producing neurosecretory cells in the locust corpus cardiacum. Microscopy Research and Technique 56 227 236

57. DumonteilE

MagnanC

Ritz-LaserB

KtorzaA

MedaP

2000 Glucose regulates proinsulin and prosomatostatin but not proglucagon messenger ribonucleic acid levels in rat pancreatic islets. Endocrinology 141 174 180

58. MagnanC

PhilippeJ

KassisN

LauryMC

PenicaudL

1995 In vivo effects of glucose and insulin on secretion and gene expression of glucagon in rats. Endocrinology 136 5370 5376

59. WebbGC

DeyA

WangJ

SteinJ

MilewskiM

2004 Altered proglucagon processing in an alpha-cell line derived from prohormone convertase 2 null mouse islets. Journal of Biological Chemistry 279 31068 31075

60. Helfrich-ForsterC

TauberM

ParkJH

Muhlig-VersenM

SchneuwlyS

2000 Ectopic expression of the neuropeptide pigment-dispersing factor alters behavioral rhythms in Drosophila melanogaster. J Neurosci 20 3339 3353

61. BrandAH

PerrimonN

1993 Targeted Gene Expression as a means of altering cell fates and generating dominant phenotypes. Development 118 401 415

62. CaiHN

ArnostiDN

LevineM