#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

An ER Complex of ODR-4 and ODR-8/Ufm1 Specific Protease 2 Promotes GPCR Maturation by a Ufm1-Independent Mechanism


Despite the importance of G-protein coupled receptors (GPCRs), we know little about their biogenesis. Olfactory receptors form a large and divergent group of GPCRs. We investigate their biogenesis in C. elegans. We show that maturation of a subset of these GPCRs, including the diacetyl receptor ODR-10, requires Ufm1 specific protease 2 (UfSP2), which corresponds to odr-8. Biochemical studies suggest mouse UfSP2 activates the Ubiquitin-like molecule Ufm1 and cleaves it from protein conjugates. However, neither the protease active site nor ufm-1 is required for UfSP2/ODR-8 to promote ODR-10 maturation. C. elegans UfSP2 is expressed in the same chemosensory neurons as ODR-4, a tail-anchored transmembrane protein also required for ODR-10 maturation. ODR-4 resides in the endoplasmic reticulum (ER); UfSP2 is cytosolic but associates with ER membranes. In odr-4 and odr-8 mutants ODR-10-GFP is retained in the ER, suggesting these genes are required to fold GPCRs or traffic them out of the ER. ODR-4 interacts biochemically with ODR-8 and ODR-10 to form an ER complex. ODR-4 and UfSP2 are conserved from plants to man, and human ODR4 can bind human UfSP2 and recruit it to ER membranes. Both proteins are expressed widely in mammals, suggesting a broader role in GPCR biogenesis.


Vyšlo v časopise: An ER Complex of ODR-4 and ODR-8/Ufm1 Specific Protease 2 Promotes GPCR Maturation by a Ufm1-Independent Mechanism. PLoS Genet 10(3): e32767. doi:10.1371/journal.pgen.1004082
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004082

Souhrn

Despite the importance of G-protein coupled receptors (GPCRs), we know little about their biogenesis. Olfactory receptors form a large and divergent group of GPCRs. We investigate their biogenesis in C. elegans. We show that maturation of a subset of these GPCRs, including the diacetyl receptor ODR-10, requires Ufm1 specific protease 2 (UfSP2), which corresponds to odr-8. Biochemical studies suggest mouse UfSP2 activates the Ubiquitin-like molecule Ufm1 and cleaves it from protein conjugates. However, neither the protease active site nor ufm-1 is required for UfSP2/ODR-8 to promote ODR-10 maturation. C. elegans UfSP2 is expressed in the same chemosensory neurons as ODR-4, a tail-anchored transmembrane protein also required for ODR-10 maturation. ODR-4 resides in the endoplasmic reticulum (ER); UfSP2 is cytosolic but associates with ER membranes. In odr-4 and odr-8 mutants ODR-10-GFP is retained in the ER, suggesting these genes are required to fold GPCRs or traffic them out of the ER. ODR-4 interacts biochemically with ODR-8 and ODR-10 to form an ER complex. ODR-4 and UfSP2 are conserved from plants to man, and human ODR4 can bind human UfSP2 and recruit it to ER membranes. Both proteins are expressed widely in mammals, suggesting a broader role in GPCR biogenesis.


Zdroje

1. BuchbergerA, BukauB, SommerT (2010) Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms. Mol Cell 40: 238–252.

2. RosenbaumEE, BrehmKS, VasiljevicE, LiuCH, HardieRC, et al. (2011) XPORT-dependent transport of TRP and rhodopsin. Neuron 72: 602–615.

3. HaleviS, McKayJ, PalfreymanM, YassinL, EshelM, et al. (2002) The C. elegans ric-3 gene is required for maturation of nicotinic acetylcholine receptors. EMBO J 21: 1012–1020.

4. MuchowskiPJ, WackerJL (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6: 11–22.

5. VenkatakrishnanAJ, DeupiX, LebonG, TateCG, SchertlerGF, et al. (2013) Molecular signatures of G-protein-coupled receptors. Nature 494: 185–194.

6. ParkE, RapoportTA (2012) Mechanisms of Sec61/SecY-mediated protein translocation across membranes. Annu Rev Biophys 41: 21–40.

7. MizrachiD, SegaloffDL (2004) Intracellularly located misfolded glycoprotein hormone receptors associate with different chaperone proteins than their cognate wild-type receptors. Mol Endocrinol 18: 1768–1777.

8. MorelloJP, SalahpourA, Petaja-RepoUE, LaperriereA, LonerganM, et al. (2001) Association of calnexin with wild type and mutant AVPR2 that causes nephrogenic diabetes insipidus. Biochemistry 40: 6766–6775.

9. LuM, EcheverriF, MoyerBD (2003) Endoplasmic reticulum retention, degradation, and aggregation of olfactory G-protein coupled receptors. Traffic 4: 416–433.

10. SaitoH, KubotaM, RobertsRW, ChiQ, MatsunamiH (2004) RTP family members induce functional expression of mammalian odorant receptors. Cell 119: 679–691.

11. StamnesMA, ShiehBH, ChumanL, HarrisGL, ZukerCS (1991) The cyclophilin homolog ninaA is a tissue-specific integral membrane protein required for the proper synthesis of a subset of Drosophila rhodopsins. Cell 65: 219–227.

12. BermakJC, LiM, BullockC, ZhouQY (2001) Regulation of transport of the dopamine D1 receptor by a new membrane-associated ER protein. Nat Cell Biol 3: 492–498.

13. HurtCM, HoVK, AngelottiT (2013) Systematic and quantitative analysis of G protein-coupled receptor trafficking motifs. Methods Enzymol 521: 171–187.

14. MendesHF, ZaccariniR, CheethamME (2010) Pharmacological manipulation of rhodopsin retinitis pigmentosa. Adv Exp Med Biol 664: 317–323.

15. MorelloJP, BichetDG (2001) Nephrogenic diabetes insipidus. Annu Rev Physiol 63: 607–630.

16. Maya-NunezG, JanovickJA, Ulloa-AguirreA, SoderlundD, ConnPM, et al. (2002) Molecular basis of hypogonadotropic hypogonadism: restoration of mutant (E(90)K) GnRH receptor function by a deletion at a distant site. J Clin Endocrinol Metab 87: 2144–2149.

17. TroemelER, ChouJH, DwyerND, ColbertHA, BargmannCI (1995) Divergent seven transmembrane receptors are candidate chemosensory receptors in C. elegans. Cell 83: 207–218.

18. ThomasJH, RobertsonHM (2008) The Caenorhabditis chemoreceptor gene families. BMC Biol 6: 42.

19. SenguptaP, ChouJH, BargmannCI (1996) odr-10 encodes a seven transmembrane domain olfactory receptor required for responses to the odorant diacetyl. Cell 84: 899–909.

20. DwyerND, TroemelER, SenguptaP, BargmannCI (1998) Odorant receptor localization to olfactory cilia is mediated by ODR-4, a novel membrane-associated protein. Cell 93: 455–466.

21. de BonoM, TobinDM, DavisMW, AveryL, BargmannCI (2002) Social feeding in Caenorhabditis elegans is induced by neurons that detect aversive stimuli. Nature 419: 899–903.

22. RogersC, PerssonA, CheungB, de BonoM (2006) Behavioral motifs and neural pathways coordinating O2 responses and aggregation in C. elegans. Curr Biol 16: 649–659.

23. KomatsuM, ChibaT, TatsumiK, IemuraS, TanidaI, et al. (2004) A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. EMBO J 23: 1977–1986.

24. SasakawaH, SakataE, YamaguchiY, KomatsuM, TatsumiK, et al. (2006) Solution structure and dynamics of Ufm1, a ubiquitin-fold modifier 1. Biochem Biophys Res Commun 343: 21–26.

25. HaBH, JeonYJ, ShinSC, TatsumiK, KomatsuM, et al. (2011) Structure of ubiquitin-fold modifier 1-specific protease UfSP2. J Biol Chem 286: 10248–10257.

26. KangSH, KimGR, SeongM, BaekSH, SeolJH, et al. (2007) Two novel ubiquitin-fold modifier 1 (Ufm1)-specific proteases, UfSP1 and UfSP2. J Biol Chem 282: 5256–5262.

27. HaBH, AhnHC, KangSH, TanakaK, ChungCH, et al. (2008) Structural basis for Ufm1 processing by UfSP1. J Biol Chem 283: 14893–14900.

28. RollsMM, HallDH, VictorM, StelzerEH, RapoportTA (2002) Targeting of rough endoplasmic reticulum membrane proteins and ribosomes in invertebrate neurons. Mol Biol Cell 13: 1778–1791.

29. WitteK, SchuhAL, HegermannJ, SarkeshikA, MayersJR, et al. (2011) TFG-1 function in protein secretion and oncogenesis. Nat Cell Biol 13: 550–558.

30. GrantB, HirshD (1999) Receptor-mediated endocytosis in the Caenorhabditis elegans oocyte. Mol Biol Cell 10: 4311–4326.

31. TreuschS, KnuthS, SlaugenhauptSA, GoldinE, GrantBD, et al. (2004) Caenorhabditis elegans functional orthologue of human protein h-mucolipin-1 is required for lysosome biogenesis. Proc Natl Acad Sci U S A 101: 4483–4488.

32. HermannGJ, SchroederLK, HiebCA, KershnerAM, RabbittsBM, et al. (2005) Genetic analysis of lysosomal trafficking in Caenorhabditis elegans. Mol Biol Cell 16: 3273–3288.

33. KaplanOI, Molla-HermanA, CevikS, GhossoubR, KidaK, et al. (2010) The AP-1 clathrin adaptor facilitates cilium formation and functions with RAB-8 in C. elegans ciliary membrane transport. J Cell Sci 123: 3966–3977.

34. DwyerND, AdlerCE, CrumpJG, L'EtoileND, BargmannCI (2001) Polarized dendritic transport and the AP-1 mu1 clathrin adaptor UNC-101 localize odorant receptors to olfactory cilia. Neuron 31: 277–287.

35. Mizuno-YamasakiE, Rivera-MolinaF, NovickP (2012) GTPase networks in membrane traffic. Annu Rev Biochem 81: 637–659.

36. DuvernayMT, FilipeanuCM, WuG (2005) The regulatory mechanisms of export trafficking of G protein-coupled receptors. Cell Signal 17: 1457–1465.

37. SumakovicM, HegermannJ, LuoL, HussonSJ, SchwarzeK, et al. (2009) UNC-108/RAB-2 and its effector RIC-19 are involved in dense core vesicle maturation in Caenorhabditis elegans. J Cell Biol 186: 897–914.

38. EdwardsSL, CharlieNK, RichmondJE, HegermannJ, EimerS, et al. (2009) Impaired dense core vesicle maturation in Caenorhabditis elegans mutants lacking Rab2. J Cell Biol 186: 881–895.

39. ChunDK, McEwenJM, BurbeaM, KaplanJM (2008) UNC-108/Rab2 regulates postendocytic trafficking in Caenorhabditis elegans. Mol Biol Cell 19: 2682–2695.

40. HertelP, DanielJ, StegehakeD, VaupelH, KailayangiriS, et al. (2013) The Ubiquitin-fold Modifier 1 (Ufm1) Cascade of Caenorhabditis elegans. J Biol Chem 288: 10661–10671.

41. ChenC, FenkLA, de BonoM (2013) Efficient genome editing in Caenorhabditis elegans by CRISPR-targeted homologous recombination. Nucleic Acids Res 41 (20) e193.

42. BrodskyJL (2012) Cleaning up: ER-associated degradation to the rescue. Cell 151: 1163–1167.

43. NakatsukasaK, HuyerG, MichaelisS, BrodskyJL (2008) Dissecting the ER-associated degradation of a misfolded polytopic membrane protein. Cell 132: 101–112.

44. ZhangZR, BonifacinoJS, HegdeRS (2013) Deubiquitinases sharpen substrate discrimination during membrane protein degradation from the ER. Cell 154: 609–622.

45. Sulston J, Hodgkin J (1988) Methods. In: Wood WB, editor. The nematode Caenorhabditis elegans. Cold Spring Harbor: CSHL Press. pp. 587–606.

46. de BonoM, BargmannCI (1998) Natural variation in a neuropeptide Y receptor homolog modifies social behavior and food response in C. elegans. Cell 94: 679–689.

47. BargmannCI, HartwiegE, HorvitzHR (1993) Odorant-selective genes and neurons mediate olfaction in C. elegans. Cell 74: 515–527.

48. CheungBH, CohenM, RogersC, AlbayramO, de BonoM (2005) Experience-dependent modulation of C. elegans behavior by ambient oxygen. Curr Biol 15: 905–917.

49. TatsumiK, SouYS, TadaN, NakamuraE, IemuraS, et al. (2010) A novel type of E3 ligase for the Ufm1 conjugation system. J Biol Chem 285: 5417–5427.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2014 Číslo 3
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#