Drosophila king tubby (ktub) mediates light-induced rhodopsin endocytosis and retinal degeneration
Tóm tắt
The tubby (tub) and tubby-like protein (tulp) genes encode a small family of proteins found in many organisms. Previous studies have shown that TUB and TULP genes in mammalian involve in obesity, neural development, and retinal degeneration. The purpose of this study was to investigate the role of Drosophila king tubby (ktub) in rhodopsin 1 (Rh1) endocytosis and retinal degeneration upon light stimulation. Drosophila ktub mutants were generated using imprecise excision. Wild type and mutant flies were raised in dark or constant light conditions. After a period of light stimulation, retinas were dissected, fixed and stained with anti-Rh1 antibody to reveal Rh1 endocytosis. Confocal and transmission electron microscope were used to examine the retinal degeneration. Immunocytochemical analysis shows that Ktub is expressed in the rhabdomere domain under dark conditions. When flies receive light stimulation, the Ktub translocates from the rhabdomere to the cytoplasm and the nucleus of the photoreceptor cells. Wild type photoreceptors form Rh1-immunopositive large vesicles (RLVs) shortly after light stimulation. In light-induced ktub mutants, the majority of Rh1 remains at the rhabdomere, and only a few RLVs appear in the cytoplasm of photoreceptor cells. Mutation of norpA allele causes massive Rh1 endocytosis in light stimulation. In ktub and norpA double mutants, however, Rh1 endocytosis is blocked under light stimulation. This study also shows that ktub and norpA double mutants rescue the light-induced norpA retinal degeneration. Deletion constructs further demonstrate that the Tubby domain of the Ktub protein participates in an important role in Rh1 endocytosis. The results in this study delimit the novel function of Ktub in Rh1 endocytosis and retinal degeneration.
Tài liệu tham khảo
Ronshaugen M, McGinnis N, Inglis D, Chou D, Zhao J, McGinnis W: Structure and expression patterns of Drosophila TULP and TUSP, members of the tubby-like gene family. Mech Dev. 2002, 117: 209-215. 10.1016/S0925-4773(02)00211-3.
Ashrafi K, Chang FY, Watts JL, Fraser AG, Kamath RS, Ahringer J, Ruvkun G: Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature. 2003, 421: 268-272. 10.1038/nature01279.
Mukhopadhyay A, Pan X, Lambright DG, Tissenbaum HA: An endocytic pathway as a target of tubby for regulation of fat storage. EMBO Rep. 2007, 8: 931-938. 10.1038/sj.embor.7401055.
Heikenwalder MF, Koritschoner NP, Pajer P, Chaboissier MC, Kurz SM, Briegel KJ, Bartunek P, Zenke M: Molecular cloning, expression and regulation of the avian tubby-like protein 1 (tulp1) gene. Gene. 2001, 273: 131-139. 10.1016/S0378-1119(01)00578-9.
Lai CP, Lee CL, Chen PH, Wu SH, Yang CC, Shaw JF: Molecular analyses of the Arabidopsis TUBBY-like protein gene family. Plant Physiol. 2004, 134: 1586-1597. 10.1104/pp.103.037820.
Yang Z, Zhou Y, Wang X, Gu S, Yu J, Liang G, Yan C, Xu C: Genomewide comparative phylogenetic and molecular evolutionary analysis of tubby-like protein family in Arabidopsis, rice, and poplar. Genomics. 2008, 92: 246-253. 10.1016/j.ygeno.2008.06.001.
North MA, Naggert JK, Yan Y, Noben-Trauth K, Nishina PM: Molecular characterization of TUB, TULP1, and TULP2, members of the novel tubby gene family and their possible relation to ocular diseases. Proc Natl Acad Sci USA. 1997, 94: 3128-3133. 10.1073/pnas.94.7.3128.
Nishina PM, North MA, Ikeda A, Yan Y, Naggert JK: Molecular characterization of a novel tubby gene family member, TULP3, in mouse and humans. Genomics. 1998, 54: 215-220. 10.1006/geno.1998.5567.
Kleyn PW, Fan W, Kovats SG, Lee JJ, Pulido JC, Wu Y, Berkemeier LR, Misumi DJ, Holmgren L, Charlat O, Woolf EA, Tayber O, Brody T, Shu P, Hawkins F, Kennedy B, Baldini L, Ebeling C, Alperin GD, Deeds J, Lakey ND, Culpepper J, Chen H, Glucksmann-Kuis MA, Carlson GA, Duyk GM, Moore KJ: Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family. Cell. 1996, 85: 281-290. 10.1016/S0092-8674(00)81104-6.
Noben-Trauth K, Naggert JK, North MA, Nishina PM: A candidate gene for the mouse mutation tubby. Nature. 1996, 380: 534-538. 10.1038/380534a0.
Ohlemiller KK, Hughes RM, Mosinger-Ogilvie J, Speck JD, Grosof DH, Silverman MS: Cochlear and retinal degeneration in the tubby mouse. Neuroreport. 1995, 6: 845-849. 10.1097/00001756-199504190-00005.
Hagstrom SA, Duyao M, North MA, Li T: Retinal degeneration in tulp1−/− mice: vesicular accumulation in the interphotoreceptor matrix. Invest Ophthalmol Vis Sci. 1999, 40: 2795-2802.
Ikeda S, Shiva N, Ikeda A, Smith RS, Nusinowitz S, Yan G, Lin TR, Chu S, Heckenlively JR, North MA, Naggert JK, Nishina PM, Duyao MP: Retinal degeneration but not obesity is observed in null mutants of the tubby-like protein 1 gene. Hum Mol Genet. 2000, 9: 155-163. 10.1093/hmg/9.2.155.
Ikeda A, Ikeda S, Gridley T, Nishina PM, Naggert JK: Neural tube defects and neuroepithelial cell death in Tulp3 knockout mice. Hum Mol Genet. 2001, 10: 1325-1334. 10.1093/hmg/10.12.1325.
Hagstrom SA, North MA, Nishina PL, Berson EL, Dryja TP: Recessive mutations in the gene encoding the tubby-like protein TULP1 in patients with retinitis pigmentosa. Nat Genet. 1998, 18: 174-176. 10.1038/ng0298-174.
Gu S, Lennon A, Li Y, Lorenz B, Fossarello M, North M, Gal A, Wright A: Tubby-like protein-1 mutations in autosomal recessive retinitis pigmentosa. Lancet. 1998, 351: 1103-1104. 10.1016/S0140-6736(05)79384-3.
Banerjee P, Kleyn PW, Knowles JA, Lewis CA, Ross BM, Parano E, Kovats SG, Lee JJ, Penchaszadeh GK, Ott J, Jacobson SG, Gilliam TC: TULP1 mutation in two extended Dominican kindreds with autosomal recessive retinitis pigmentosa. Nat Genet. 1998, 18: 177-179. 10.1038/ng0298-177.
Boggon TJ, Shan WS, Santagata S, Myers SC, Shapiro L: Implication of tubby proteins as transcription factors by structure-based functional analysis. Science. 1999, 286: 2119-2125. 10.1126/science.286.5447.2119.
Carroll K, Gomez C, Shapiro L: Tubby proteins: the plot thickens. Nat Rev Mol Cell Biol. 2004, 5: 55-63. 10.1038/nrm1278.
Xi Q, Pauer GJ, Marmorstein AD, Crabb JW, Hagstrom SA: Tubby-like protein 1 (TULP1) interacts with F-actin in photoreceptor cells. Invest Ophthalmol Vis Sci. 2005, 46: 4754-4761. 10.1167/iovs.05-0693.
Xi Q, Pauer GJ, Ball SL, Rayborn M, Hollyfield JG, Peachey NS, Crabb JW, Hagstrom SA: Interaction between the photoreceptor-specific tubby-like protein 1 and the neuronal-specific GTPase dynamin-1. Invest Ophthalmol Vis Sci. 2007, 48: 2837-2844. 10.1167/iovs.06-0059.
Hagstrom SA, Adamian M, Scimeca M, Pawlyk BS, Yue G, Li T: A role for the Tubby-like protein 1 in rhodopsin transport. Invest Ophthalmol Vis Sci. 2001, 42: 1955-1962.
Grossman GH, Pauer GJ, Narendra U, Peachey NS, Hagstrom SA: Early synaptic defects in tulp1−/− mice. Invest Ophthalmol Vis Sci. 2009, 50: 3074-3083. 10.1167/iovs.08-3190.
Caberoy NB, Li W: Unconventional secretion of tubby and tubby-like protein 1. FEBS Lett. 2009, 583: 3057-3062. 10.1016/j.febslet.2009.08.015.
Caberoy NB, Maiguel D, Kim Y, Li W: Identification of tubby and tubby-like protein 1 as eat-me signals by phage display. Exp Cell Res. 2010, 316: 245-257. 10.1016/j.yexcr.2009.10.008.
Caberoy NB, Zhou Y, Li W: Tubby and tubby-like protein 1 are new MerTK ligands for phagocytosis. EMBO J. 2010, 29: 3898-3910. 10.1038/emboj.2010.265.
Montell C: Visual transduction in Drosophila. Annu Rev Cell Dev Biol. 1999, 15: 231-268. 10.1146/annurev.cellbio.15.1.231.
Zuker CS: The biology of vision of Drosophila. Proc Natl Acad Sci USA. 1996, 93: 571-576. 10.1073/pnas.93.2.571.
Shieh BH: Molecular genetics of retinal degeneration: a Drosophila perspective. Fly (Austin). 2011, 5: 356-368.
Montell C, Rubin GM: Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction. Neuron. 1989, 2: 1313-1323. 10.1016/0896-6273(89)90069-X.
Van Vactor D, O'Reilly AM, Neel BG: Genetic analysis of protein tyrosine phosphatases. Curr Opin Genet Dev. 1998, 8: 112-126. 10.1016/S0959-437X(98)80070-1.
Kumar JP, Ready DF: Rhodopsin plays an essential structural role in Drosophila photoreceptor development. Development. 1995, 121: 4359-4370.
Bennett N, Sitaramayya A: Inactivation of photoexcited rhodopsin in retinal rods: the roles of rhodopsin kinase and 48-kDa protein (arrestin). Biochemistry. 1988, 27: 1710-1715. 10.1021/bi00405a049.
Kuhn H, Wilden U: Deactivation of photoactivated rhodopsin by rhodopsin-kinase and arrestin. J Recept Res. 1987, 7: 283-298.
Hardie RC, Raghu P: Visual transduction in Drosophila. Nature. 2001, 413: 186-1893. 10.1038/35093002.
Laporte SA, Oakley RH, Holt JA, Barak LS, Caron MG: The interaction of beta-arrestin with the AP-2 adaptor is required for the clustering of beta 2-adrenergic receptor into clathrin-coated pits. J Biol Chem. 2000, 275: 23120-23126. 10.1074/jbc.M002581200.
Satoh AK, Ready DF: Arrestin1 mediates light-dependent rhodopsin endocytosis and cell survival. Curr Biol. 2005, 15: 1722-1733. 10.1016/j.cub.2005.08.064.
Alloway PG, Howard L, Dolph PJ: The formation of stable rhodopsin-arrestin complexes induces apoptosis and photoreceptor cell degeneration. Neuron. 2000, 28: 129-138. 10.1016/S0896-6273(00)00091-X.
Kiselev A, Socolich M, Vinos J, Hardy RW, Zuker CS, Ranganathan R: A molecular pathway for light-dependent photoreceptor apoptosis in Drosophila. Neuron. 2000, 28: 139-152. 10.1016/S0896-6273(00)00092-1.
Lee SJ, Xu H, Kang LW, Amzel LM, Montell C: Light adaptation through phosphoinositide-regulated translocation of Drosophila visual arrestin. Neuron. 2003, 39: 121-132. 10.1016/S0896-6273(03)00390-8.
Yao JG, Sun YH: Eyg and Ey Pax proteins act by distinct transcriptional mechanisms in Drosophila development. EMBO J. 2005, 24: 2602-2612. 10.1038/sj.emboj.7600725.
Spradling AC, Rubin GM: Transposition of cloned P elements into Drosophila germ line chromosomes. Science. 1982, 218: 341-347. 10.1126/science.6289435.
Towbin H, Staehelin T, Gordon J: Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA. 1979, 76: 4350-4354. 10.1073/pnas.76.9.4350.
Fan SS: Dynactin affects extension and assembly of adherens junctions in Drosophila photoreceptor development. J Biomed Sci. 2004, 11: 362-369.
Lewis CA, Batlle IR, Batlle KG, Banerjee P, Cideciyan AV, Huang J, Aleman TS, Huang Y, Ott J, Gilliam TC, Knowles JA, Jacobson SG: Tubby-like protein 1 homozygous splice-site mutation causes early-onset severe retinal degeneration. Invest Ophthalmol Vis Sci. 1999, 40: 2106-2114.
Ikeda A, Zheng QY, Rosenstiel P, Maddatu T, Zuberi AR, Roopenian DC, North MA, Naggert JK, Johnson KR, Nishina PM: Genetic modification of hearing in tubby mice: evidence for the existence of a major gene (moth1) which protects tubby mice from hearing loss. Hum Mol Genet. 1999, 8: 1761-1767. 10.1093/hmg/8.9.1761.
Kong L, Li F, Soleman CE, Li S, Elias RV, Zhou X, Lewis DA, McGinnis JF, Cao W: Bright cyclic light accelerates photoreceptor cell degeneration in tubby mice. Neurobiol Dis. 2006, 21: 468-477. 10.1016/j.nbd.2005.08.017.
Acharya U, Patel S, Koundakjian E, Nagashima K, Han X, Acharya JK: Modulating sphingolipid biosynthetic pathway rescues photoreceptor degeneration. Science. 2003, 299: 1740-1743. 10.1126/science.1080549.
Orem NR, Dolph PJ: Epitope masking of rhabdomeric rhodopsin during endocytosis-induced retinal degeneration. Mol Vis. 2002, 8: 455-461.
Hsu CD, Whaley MA, Frazer K, Miller DA, Mitchell KA, Adams SM, O'Tousa JE: Limited role of developmental programmed cell death pathways in Drosophila norpA retinal degeneration. J Neurosci. 2004, 24: 500-507. 10.1523/JNEUROSCI.3328-02.2004.
Vinos J, Jalink K, Hardy RW, Britt SG, Zuker CS: A G protein-coupled receptor phosphatase required for rhodopsin function. Science. 1997, 277: 687-690. 10.1126/science.277.5326.687.
Lee SJ, Xu H, Montell C: Rhodopsin kinase activity modulates the amplitude of the visual response in Drosophila. Proc Natl Acad Sci USA. 2004, 101: 11874-11879. 10.1073/pnas.0402205101.
Orem NR, Xia L, Dolph PJ: An essential role for endocytosis of rhodopsin through interaction of visual arrestin with the AP-2 adaptor. J Cell Sci. 2006, 119: 3141-3148. 10.1242/jcs.03052.
Dolph PJ, Ranganathan R, Colley NJ, Hardy RW, Socolich M, Zuker CS: Arrestin function in inactivation of G protein-coupled receptor rhodopsin in vivo. Science. 1993, 260: 1910-1916. 10.1126/science.8316831.
Orem NR, Dolph PJ: Loss of the phospholipase C gene product induces massive endocytosis of rhodopsin and arrestin in Drosophila photoreceptors. Vision Res. 2002, 42: 497-505. 10.1016/S0042-6989(01)00229-2.
Van der Bliek AM: Functional diversity in the dynamin family. Trends Cell Biol. 1999, 9: 96-102. 10.1016/S0962-8924(98)01490-1.
McNiven MA, Kim L, Krueger EW, Orth JD, Cao H, Wong TW: Regulated interactions between dynamin and the actin-binding protein cortactin modulate cell shape. J Cell Biol. 2000, 151: 187-198. 10.1083/jcb.151.1.187.
Tomizawa K, Sunada S, Lu YF, Oda Y, Kinuta M, Ohshima T, Saito T, Wei FY, Matsushita M, Li ST, Tsutsui K, Hisanaga S, Mikoshiba K, Takei K, Matsui H: Cophosphorylation of amphiphysin I and dynamin I by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles. J Cell Biol. 2003, 163: 813-824. 10.1083/jcb.200308110.