Inactivation of VCP/ter94 Suppresses Retinal Pathology Caused by Misfolded Rhodopsin in

English version České info

The most common Rhodopsin (Rh) mutation associated with autosomal dominant retinitis pigmentosa (ADRP) in North America is the substitution of proline 23 by histidine (Rh^P23H). Unlike the wild-type Rh, mutant Rh^P23H exhibits folding defects and forms intracellular aggregates. The mechanisms responsible for the recognition and clearance of misfolded Rh^P23H and their relevance to photoreceptor neuron (PN) degeneration are poorly understood. Folding-deficient membrane proteins are subjected to Endoplasmic Reticulum (ER) quality control, and we have recently shown that Rh^P23H is a substrate of the ER–associated degradation (ERAD) effector VCP/ter94, a chaperone that extracts misfolded proteins from the ER (a process called retrotranslocation) and facilitates their proteasomal degradation. Here, we used Drosophila, in which Rh1^P37H (the equivalent of mammalian Rh^P23H) is expressed in PNs, and found that the endogenous Rh1 is required for Rh1^P37H toxicity. Genetic inactivation of VCP increased the levels of misfolded Rh1^P37H and further activated the Ire1/Xbp1 ER stress pathway in the Rh1^P37H retina. Despite this, Rh1^P37H flies with decreased VCP function displayed a potent suppression of retinal degeneration and blindness, indicating that VCP activity promotes neurodegeneration in the Rh1^P37H retina. Pharmacological treatment of Rh1^P37H flies with the VCP/ERAD inhibitor Eeyarestatin I or with the proteasome inhibitor MG132 also led to a strong suppression of retinal degeneration. Collectively, our findings raise the possibility that excessive retrotranslocation and/or degradation of visual pigment is a primary cause of PN degeneration.

Vyšlo v časopise: Inactivation of VCP/ter94 Suppresses Retinal Pathology Caused by Misfolded Rhodopsin in. PLoS Genet 6(8): e32767. doi:10.1371/journal.pgen.1001075
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001075

Souhrn

Zdroje

1. PowersET

MorimotoRI

DillinA

KellyJW

BalchWE

2009 Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 78 959 991

2. DaigerSP

BowneSJ

SullivanLS

2007 Perspective on genes and mutations causing retinitis pigmentosa. Arch Ophthalmol 125 151 158

3. KennanA

AherneA

HumphriesP

2005 Light in retinitis pigmentosa. Trends Genet 21 103 110

4. FarrarGJ

KennaPF

HumphriesP

2002 On the genetics of retinitis pigmentosa and on mutation-independent approaches to therapeutic intervention. EMBO J 21 857 864

5. ChappleJP

GraysonC

HardcastleAJ

SalibaRS

van der SpuyJ

2001 Unfolding retinal dystrophies: a role for molecular chaperones? Trends Mol Med 7 414 421

6. DaigerSP

2004 Identifying retinal disease genes: how far have we come, how far do we have to go? Novartis Found Symp 255 17 27; discussion 27–36, 177–8

7. MendesHF

van der SpuyJ

ChappleJP

CheethamME

2005 Mechanisms of cell death in rhodopsin retinitis pigmentosa: implications for therapy. Trends Mol Med 11 177 185

8. NaashMI

HollyfieldJG

al-UbaidiMR

BaehrW

1993 Simulation of human autosomal dominant retinitis pigmentosa in transgenic mice expressing a mutated murine opsin gene. Proc Natl Acad Sci USA 90 5499 5503

9. KosmaoglouM

SchwarzN

BettJS

CheethamME

2008 Molecular chaperones and photoreceptor function. Prog Retin Eye Res 27 434 449

10. KaushalS

KhoranaHG

1994 Structure and function in rhodopsin. 7. Point mutations associated with autosomal dominant retinitis pigmentosa. Biochemistry 33 6121 6128

11. GalyA

RouxMJ

SahelJA

LéveillardT

GiangrandeA

2005 Rhodopsin maturation defects induce photoreceptor death by apoptosis: a fly model for RhodopsinPro23His human retinitis pigmentosa. Hum Mol Genet 14 2547 2557

12. MendesHF

CheethamME

2008 Pharmacological manipulation of gain-of-function and dominant-negative mechanisms in rhodopsin retinitis pigmentosa. Hum Mol Genet 17 3043 3054

13. SungCH

SchneiderBG

AgarwalN

PapermasterDS

NathansJ

1991 Functional heterogeneity of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci USA 88 8840 8844

14. IllingME

RajanRS

BenceNF

KopitoRR

2002 A rhodopsin mutant linked to autosomal dominant retinitis pigmentosa is prone to aggregate and interacts with the ubiquitin proteasome system. J Biol Chem 277 34150 34160

15. SalibaRS

MunroPM

LuthertPJ

CheethamME

2002 The cellular fate of mutant rhodopsin: quality control, degradation and aggresome formation. J Cell Sci 115 2907 2918

16. GriciucA

AronL

PiccoliG

UeffingM

2010 Clearance of Rhodopsin(P23H) aggregates requires the ERAD effector VCP. Biochim Biophys Acta 1803 424 434

17. BernalesS

PapaFR

WalterP

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

18. LinJH

LiH

YasumuraD

CohenHR

ZhangC

2007 IRE1 signaling affects cell fate during the unfolded protein response. Science 318 944 949

19. RonD

WalterP

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

20. MendesCS

LevetC

ChatelainG

DourlenP

FouilletA

2009 ER stress protects from retinal degeneration. EMBO J 28 1296 1307

21. RömischK

2005 Endoplasmic reticulum-associated degradation. Annu Rev Cell Dev Biol 21 435 456

22. VembarSS

BrodskyJL

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

23. DaiRM

LiCC

2001 Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation. Nat Cell Biol 3 740 744

24. YeY

MeyerHH

RapoportTA

2001 The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414 652 656

25. DeLaBarreB

ChristiansonJC

KopitoRR

BrungerAT

2006 Central pore residues mediate the p97/VCP activity required for ERAD. Mol Cell 22 451 462

26. SongC

WangQ

LiCC

2003 ATPase activity of p97-valosin-containing protein (VCP). D2 mediates the major enzyme activity, and D1 contributes to the heat-induced activity. J Biol Chem 278 3648 3655

27. WangQ

SongC

LiCC

2004 Molecular perspectives on p97-VCP: progress in understanding its structure and diverse biological functions. J Struct Biol 146 44 57

28. VijN

FangS

ZeitlinPL

2006 Selective inhibition of endoplasmic reticulum-associated degradation rescues DeltaF508-cystic fibrosis transmembrane regulator and suppresses interleukin-8 levels: therapeutic implications. J Biol Chem 281 17369 17378

29. SchwiegerI

LautzK

KrauseE

RosenthalW

WiesnerB

2008 Derlin-1 and p97/valosin-containing protein mediate the endoplasmic reticulum-associated degradation of human V2 vasopressin receptors. Mol Pharmacol 73 697 708

30. BoeddrichA

GaumerS

HaackeA

TzvetkovN

AlbrechtM

2006 An arginine/lysine-rich motif is crucial for VCP/p97-mediated modulation of ataxin-3 fibrillogenesis. EMBO J 25 1547 1558

31. GitchoMA

StriderJ

CarterD

Taylor-ReinwaldL

FormanMS

2009 VCP mutations causing frontotemporal lobar degeneration disrupt localization of TDP-43 and induce cell death. J Biol Chem 284 12384 12398

32. MizunoY

HoriS

KakizukaA

OkamotoK

2003 Vacuole-creating protein in neurodegenerative diseases in humans. Neurosci Lett 343 77 80

33. ColleyNJ

CassillJA

BakerEK

ZukerCS

1995 Defective intracellular transport is the molecular basis of rhodopsin-dependent dominant retinal degeneration. Proc.Natl Acad Sc USA 92 3070 3074

34. KuradaP

O'TousaJE

1995 Retinal degeneration caused by dominant rhodopsin mutations in Drosophila. Neuron 14 571 579

35. KuradaP

ToniniTD

SerikakuMA

PicciniJP

O'TousaJE

1998 Rhodopsin maturation antagonized by dominant rhodopsin mutants. Vis Neurosci 15 693 700

36. RajanRS

KopitoRR

2005 Suppression of wild-type rhodopsin maturation by mutants linked to autosomal dominant retinitis pigmentosa. J Biol Chem 280 1284 1291

37. RyooHD

DomingosPM

KangMJ

StellerH

2007 Unfolded protein response in a Drosophila model for retinal degeneration. EMBO J 26 242 252

38. CrowMK

KarasavvasN

SarrisAH

2001 Protein aggregation mediated by cysteine oxidation during the stacking phase of discontinuous buffer SDS-PAGE. Biotechniques 30 311 316

39. LeeSJ

MontellC

2004 Suppression of constant-light-induced blindness but not retinal degeneration by inhibition of the rhodopsin degradation pathway. Curr Biol 14 2076 2085

40. RudenDM

SollarsV

WangX

MoriD

AltermanM

2000 Membrane fusion proteins are required for oskar mRNA localization in the Drosophila egg chamber. Dev Biol 218 314 325

41. KosmaoglouM

KanugaN

AguilàM

GarrigaP

CheethamME

2009 A dual role for EDEM1 in the processing of rod opsin. J Cell Sci 122 4465 7442

42. YoshidaH

MatsuiT

YamamotoA

OkadaT

MoriK

2001 XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107 881 891

43. SzegezdiE

LogueSE

GormanAM

SamaliA

2006 Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7 880 885

44. FiebigerE

HirschC

VyasJM

GordonE

PloeghHL

2004 Dissection of the dislocation pathway for type I membrane proteins with a new small molecule inhibitor, eeyarestatin. Mol Biol Cell 15 1635 1646

45. WangQ

LiL

YeY

2008 Inhibition of p97-dependent protein degradation by Eeyarestatin I. J Biol Chem 283 7445 7454

46. MuroI

HayBA

ClemRJ

2002 The Drosophila DIAP1 protein is required to prevent accumulation of a continuously generated, processed form of the apical caspase DRONC. J Biol Chem 277 49644 49650

47. LundgrenJ

MassonP

MirzaeiZ

YoungP

2005 Identification and characterization of a Drosophila proteasome regulatory network. Mol Cell Biol 25 4662 4675

48. HirschJ

BoudreauJC

1958 Studies in experimental behaviour genetics. I. The heritability of phototaxis in a population of Drosophila melanogaster. J Comp Physiol Psychol 51 647 651

49. BenzerS

1967 Behavioral mutants of Drosophila isolated by countercurrent distribution. Proc Natl Acad Sci USA 58 1112 1119

50. PakWL

1979 Study of photoreceptor function using Drosophila mutants. 67 99 In Neurogenetics: Genetic Approaches to the Nervous System, XO Breakefield, ed. (New York: Elsevier)

51. JuJS

FuentealbaRA

MillerSE

JacksonE

Piwnica-WormsD

2009 Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol 187 875 888

52. JuJS

WeihlCC

2010 Inclusion body myopathy, Paget's disease of the bone and fronto-temporal dementia: a disorder of autophagy. Hum Mol Genet 19 R38 45

53. TresseE

SalomonsFA

VesaJ

BottLC

KimonisV

2010 VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy 6 217 227

54. JastrzebskaB

FotiadisD

JangGF

StenkampRE

EngelA

2006 Functional and structural characterization of rhodopsin oligomers. J Biol Chem 281 11917 11922

55. ShukolyukovSA

2009 Aggregation of frog rhodopsin to oligomers and their dissociation to monomer: application of BN- and SDS-PAGE. Biochemistry (Mosc) 74 599 604

56. LindgrenM

HammarströmP

2010 Amyloid oligomers: spectroscopic characterization of amyloidogenic protein states. FEBS J 277 1380 1388

57. GoldeTE

EckmanCB

YounkinSG

2000 Biochemical detection of Abeta isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer's disease. Biochim Biophys Acta 1502 172 187

58. FrederickJM

KrasnoperovaNV

HoffmannK

Church-KopishJ

RütherK

2001 Mutant rhodopsin transgene expression on a null background. Invest Ophthalmol Vis Sci 42 826 833

59. OlssonJE

GordonJW

PawlykBS

RoofD

HayesA

1992 Transgenic mice with a rhodopsin mutation (Pro23His): a mouse model of autosomal dominant retinitis pigmentosa. Neuron 9 815 830

60. NaashML

PeacheyNS

LiZY

GryczanCC

GotoY

1996 Light-induced acceleration of photoreceptor degeneration in transgenic mice expressing mutant rhodopsin. Invest Ophthalmol Vis Sci 37 775 782

61. WangM

LamTT

TsoMO

NaashMI

1997 Expression of a mutant opsin gene increases the susceptibility of the retina to light damage. Vis Neurosci 14 55 62

62. ChillarónJ

HaasIG

2000 Dissociation from BiP and retrotranslocation of unassembled immunoglobulin light chains are tightly coupled to proteasome activity. Mol Biol Cell 11 217 226

63. ManciniR

FagioliC

FraAM

MaggioniC

SitiaR

2000 Degradation of unassembled soluble Ig subunits by cytosolic proteasomes: evidence that retrotranslocation and degradation are coupled events. FASEB J 14 769 778

64. SatohAK

ReadyDF

2005 Arrestin1 mediates light-dependent rhodopsin endocytosis and cell survival. Curr Biol 15 1722 1733

65. KangMJ

RyooHD

2009 Suppression of retinal degeneration in Drosophila by stimulation of ER-associated degradation. Proc Natl Acad Sci USA 106 17043 17048

66. NedelskyNB

ToddPK

TaylorJP

2008 Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection. Biochim Biophys Acta 1782 691 699

67. PandeyUB

NieZ

BatleviY

McCrayBA

RitsonGP

2007 HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447 859 863

68. BoyaultC

GilquinB

ZhangY

RybinV

GarmanE

2006 HDAC6-p97/VCP controlled polyubiquitin chain turnover. EMBO J 25 3357 3366

69. WangT

LaoU

EdgarBA

2009 TOR-mediated autophagy regulates cell death in Drosophila neurodegenerative disease. J Cell Biol 186 703 711

70. GorbatyukMS

KnoxT

LaVailMM

GorbatyukOS

NoorwezSM

2010 Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78. Proc Natl Acad Sci USA 107 5961 5966

71. KimonisVE

WattsGD

2005 Autosomal dominant inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Alzheimer Dis Assoc Disord Suppl 1 S44 47

72. KimonisVE

FulchieroE

VesaJ

WattsG

2008 VCP disease associated with myopathy, Paget disease of bone and frontotemporal dementia: review of a unique disorder. Biochim Biophys Acta 1782 744 748

73. KyptaRM

SuH

ReichardtLF

1996 Association between a transmembrane protein tyrosine phosphatase and the cadherin-catenin complex. J Cell Biol 134 1519 1529

74. OrmeMH

AlrubaieS

BradleyGL

WalkerCD

LeeversSJ

2006 Input from Ras is required for maximal PI(3)K signalling in Drosophila. Nat Cell Biol 8 1298 1302

75. SatohA

TokunagaF