Abstract
Retrotransposons and retroviral insertions have molded the genomes of many eukaryotes. Since retroelements transpose via an RNA intermediate, the additive nature of the replication cycle can result in massive increases in copy number if left unchecked. Host organisms have countered with several defense systems, including domestication of retroelement genes that now act as restriction factors to minimize propagation. We discovered a novel truncated form of the Saccharomyces Ty1 retrotransposon capsid protein, dubbed p22 that inhibits virus-like particle (VLP) assembly and function. The p22 restriction factor expands the repertoire of defense proteins targeting the capsid and highlights a novel host–parasite strategy. Instead of inhibiting all transposition by domesticating the restriction gene as a distinct locus, Ty1 and budding yeast may have coevolved a relationship that allows high levels of transposition when Ty1 copy numbers are low and progressively less transposition as copy numbers rise. Here, we offer a perspective on p22 restriction, including its mode of expression, effect on VLP functions, interactions with its target, properties as a nucleic acid chaperone, similarities to other restriction factors, and future directions.
Similar content being viewed by others
References
Adams SE, Mellor J, Gull K, Sim RB, Tuite MF, Kingsman SM, Kingsman AJ (1987) The functions and relationships of Ty-VLP proteins in yeast reflect those of mammalian retroviral proteins. Cell 49:111–119
AL-Khayat HA, Bhella D, Kenney JM, Roth JF, Kingsman AJ, Martin-Rendon E, Saibil HR (1999) Yeast Ty retrotransposons assemble into virus-like particles whose T-numbers depend on the C-terminal length of the capsid protein. J Mol Biol 292:65–73
Armezzani A, Arnaud F, Caporale M, di Meo G, Iannuzzi L, Murgia C, Palmarini M (2011) The signal peptide of a recently integrated endogenous sheep betaretrovirus envelope plays a major role in eluding Gag-mediated late restriction. J Virol 85:7118–7128. doi:10.1128/JVI.00407-11
Arnaud F, Murcia PR, Palmarini M (2007) Mechanisms of late restriction induced by an endogenous retrovirus. J Virol 81:11441–11451. doi:10.1128/JVI.01214-07
Arribere JA, Gilbert WV (2013) Roles for transcript leaders in translation and mRNA decay revealed by transcript leader sequencing. Genome Res 23:977–987. doi:10.1101/gr.150342.112
Bai X-C, McMullan G, Scheres SHW (2015) How cryo-EM is revolutionizing structural biology. Trend Biochem Sci 40:49–57. doi:10.1016/j.tibs.2014.10.005
Baller JA, Gao J, Stamenova R, Curcio MJ, Voytas DF (2012) A nucleosomal surface defines an integration hotspot for the Saccharomyces cerevisiae Ty1 retrotransposon. Genome Res 22:704–713. doi:10.1101/gr.129585.111
Beliakova-Bethell N, Beckham C, Giddings TH, Winey M, Parker R, Sandmeyer S (2006) Virus-like particles of the Ty3 retrotransposon assemble in association with P-body components. RNA 12:94–101. doi:10.1261/rna.2264806
Benit L, De Parseval N, Casella JF, Callebaut I, Cordonnier A, Heidmann T (1997) Cloning of a new murine endogenous retrovirus, MuERV-L, with strong similarity to the human HERV-L element and with a Gag coding sequence closely related to the Fv1 restriction gene. J Virol 71:5652–5657
Berretta J, Pinskaya M, Morillon A (2008) A cryptic unstable transcript mediates transcriptional trans-silencing of the Ty1 retrotransposon in S. cerevisiae. Gene Dev 22:615–626. doi:10.1101/gad.458008
Best S, Le Tissier P, Towers G, Stoye JP (1996) Positional cloning of the mouse retrovirus restriction gene Fv1. Nature 382:826–829. doi:10.1038/382826a0
Bilanchone V, Clemens K, Kaake R, Dawson AR, Matheos D, Nagashima K, Sitlani P, Patterson K, Chang I, Huang L, Sandmeyer S (2015) Ty3 retrotransposon hijacks mating yeast RNA processing bodies to infect new genomes. PLoS Genet 11:e1005528
Boeke JD, Garfinkel DJ, Styles CA, Fink GR (1985) Ty elements transpose through an RNA intermediate. Cell 40:491–500
Bridier-Nahmias A, Tchalikian-Cosson A, Baller JA, Menouni R, Fayol H, Flores A, Saïb A, Werner M, Voytas DF, Lesage P (2015) An RNA polymerase III subunit determines sites of retrotransposon integration. Science 348:585–588. doi:10.1126/science.1259114
Burns N, Saibil H, White N, Pardon J, Timmins P, Richardson S, Richards B, Adams S, Kingsman S, Kingsman A (1992) Symmetry, flexibility and permeability in the structure of yeast retrotransposon virus-like particles. EMBO J 11:1155–1164
Cavener DR, Ray SC (1991) Eukaryotic start and stop translation sites. Nucleic Acid Res 19:3185–3192
Checkley MA, Nagashima K, Lockett SJ, Nyswaner KM, Garfinkel DJ (2010) P-body components are required for Ty1 retrotransposition during assembly of retrotransposition-competent virus-like particles. Mol Cell Biol 30:382–398. doi:10.1128/MCB.00251-09
Checkley MA, Mitchell JA, Eizenstat LD, Lockett SJ, Garfinkel DJ (2013) Ty1 Gag enhances the stability and nuclear export of Ty1 mRNA. Traffic 14:57–69. doi:10.1111/tra.12013
Craig NL (1990) P element transposition. Cell 62:399–402
Cristofari G, Ficheux D, Darlix J-L (2000) The Gag-like protein of the yeast Ty1 retrotransposon contains a nucleic acid chaperone domain analogous to retroviral nucleocapsid proteins. J Biol Chem 275:19210–19217. doi:10.1074/jbc.M001371200
Curcio MJ, Garfinkel DJ (1991a) Regulation of retrotransposition in Saccharomyces cerevisiae. Mol Microbiol 5:1823–1829
Curcio MJ, Garfinkel DJ (1991b) Single-step selection for Ty1 element retrotransposition. Proc Natl Acad Sci USA 88:936–940
Curcio MJ, Garfinkel DJ (1992) Posttranslational control of Ty1 retrotransposition occurs at the level of protein processing. Mol Cell Biol 12:2813–2825
Curcio MJ, Garfinkel DJ (1994) Heterogeneous functional Ty1 elements are abundant in the Saccharomyces cerevisiae genome. Genetics 136:1245–1259
Curcio MJ, Lutz S, Lesage P (2015) The Ty1 LTR-retrotransposon of budding yeast. Microbiol spectr 3:1–35. doi:10.1128/microbiolspec.MDNA3-0053-2014
Devine SE, Boeke JD (1996) Integration of the yeast retrotransposon Ty1 is targeted to regions upstream of genes transcribed by RNA polymerase III. Gene Dev 10:620–633
Doh JH, Lutz S, Curcio MJ (2014) Co-translational localization of an LTR-retrotransposon RNA to the endoplasmic reticulum nucleates virus-like particle assembly sites. PLoS Genet 10:e1004219. doi:10.1371/journal.pgen.1004219
Drinnenberg IA, Weinberg DE, Xie KT, Mower JP, Wolfe KH, Fink GR, Bartel D (2009) RNAi in budding yeast. Science 326:544–550. doi:10.1126/science.1176945
Drinnenberg IA, Fink GR, Bartel DP (2011) Compatibility with killer explains the rise of RNAi-deficient fungi. Science 333:1592. doi:10.1126/science.1209575
Dutko JA, Kenny AE, Gamache ER, Curcio MJ (2010) 5′ and 3′ mRNA decay factors colocalize with Ty1 Gag and human APOBEC3G and promote Ty1 retrotransposition. J Virol 84:5052–5066. doi:10.1128/JVI.02477-09
Farabaugh PJ (1995) Post-transcriptional regulation of transposition by Ty retrotransposons of Saccharomyces cerevisiae. J Biol Chem 270:10361–10364
Fink GR, Boeke JD, Garfinkel DJ (1986) The mechanism and consequences of retrotransposition. Trends in Genetics. 2:118–123
Fricke T, White TE, Schulte B, de Souza Aranha Vieira DA, Dharan A, Campbell EM, Brandariz-Nunez A, Diaz-Griffero F (2014) MxB binds to the HIV-1 core and prevents the uncoating process of HIV-1. Retrovirology 11:68. doi:10.1186/PREACCEPT-6453674081373986
Garfinkel DJ, Boeke JD, Fink GR (1985) Ty element transposition: reverse transcriptase and virus-like particles. Cell 42:502–517
Garfinkel DJ, Nyswaner K, Wang J, Cho J-Y (2003) Post-transcriptional cosuppression of Ty1 retrotransposition. Genetics 165:83–99
Goldstone DC, Walker PA, Calder LJ, Coombs PJ, Kirkpatrick J, Ball NJ, Hilditch L, Yap MW, Rosenthal PB, Stoye JP, Taylor IA (2014) Structural studies of postentry restriction factors reveal antiparallel dimers that enable avid binding to the HIV-1 capsid lattice. Proc Natl Acad Sci USA 111:9609–9614. doi:10.1073/pnas.1402448111
Goodier J, Kazazian H (2008) Retrotransposons revisited: the restraint and rehabilitation of parasites. Cell 135:23–35
Grant PA, Duggan L, Côté J, Roberts SM, Brownell JE, Candau R, Ohba R, Owen-Hughes T, Allis CD, Winston F, Berger SL, Workman JL (1997) Yeast Gcn5 functions in two multisubunit complexes to acetylate nucleosomal histones: characterization of an Ada complex and the SAGA (Spt/Ada) complex. Gene Dev 11:1640–1650
Haimovich G, Medina DA, Causse SZ, Garber M, Millán-Zambrano G, Barkai O, Chávez S, Pérez-Ortín JE, Darzacq X, Choder M (2013) Gene expression is circular: factors for mRNA degradation also foster mRNA synthesis. Cell 153:1000–1011. doi:10.1016/j.cell.2013.05.012
Harris RS, Hultquist JF, Evans DT (2012) The restriction factors of human immunodeficiency virus. J Biol Chem 287:40875–40883. doi:10.1074/jbc.R112.416925
Hilditch L, Matadeen R, Goldstone DC, Rosenthal PB, Taylor IA, Stoye JP (2011) Ordered assembly of murine leukemia virus capsid protein on lipid nanotubes directs specific binding by the restriction factor, Fv1. Proc Natl Acad Sci USA 108:5771–5776. doi:10.1073/pnas.1100118108
Ingolia NT, Ghaemmaghami S, Newman JR, Weissman JS (2009) Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324:218–223. doi:10.1126/science.1168978
Jern P, Coffin JM (2008) Effects of retroviruses on host genome function. Annu Rev Genet 42:709–732
Kaneko-Ishino T, Ishino F (2012) The role of genes domesticated from LTR retrotransposons and retroviruses in mammals. Front Microbiol 3:262. doi:10.3389/fmicb.2012.00262
Keeney JB, Chapman KB, Lauermann V, Voytas DF, Aström SU, von Pawel-Rammingen U, Bystrom A, Boeke JD (1995) Multiple molecular determinants for retrotransposition in a primer tRNA. Mol Cell Biol 15:217–226
Kenna MA, Brachmann CB, Devine SE, Boeke JD (1998) Invading the yeast nucleus: a nuclear localization signal at the C terminus of Ty1 integrase is required for transposition in vivo. Mol Cell Biol 18:1115–1124
Kim JM, Vanguri S, Boeke JD, Gabriel A, Voytas DF (1998) Transposable elements and genome organization: a comprehensive survey of retrotransposons revealed by the complete Saccharomyces cerevisiae genome sequence. Genome Res 8:464–478
Lee S-I, Kim N-S (2014) Transposable elements and genome size variations in plants. Genom Inf 12:87–97
Leroux C, Girard N, Cottin V, Greenland T, Mornex J-F, Archer F (2007) Jaagsiekte sheep retrovirus (JSRV): from virus to lung cancer in sheep. Vet Res 38:211–228. doi:10.1051/vetres:2006060
Malagon F, Jensen TH (2008) The T body, a new cytoplasmic RNA granule in Saccharomyces cerevisiae. Mol Cell Biol 28:6022–6032. doi:10.1128/MCB.00684-08
Malim MH, Bieniasz PD (2012) HIV restriction factors and mechanisms of evasion. Cold Spring Harb Perspect Med 2:a006940. doi:10.1101/cshperspect.a006940
Matsuda E, Garfinkel DJ (2009) Posttranslational interference of Ty1 retrotransposition by antisense RNAs. Proc Natl Acad Sci USA 106:15657–15662. doi:10.1073/pnas.0908305106
McLane LM, Pulliam KF, Devine SE, Corbett AH (2008) The Ty1 integrase protein can exploit the classical nuclear protein import machinery for entry into the nucleus. Nucleic Acid Res 36:4317–4326. doi:10.1093/nar/gkn383
Moore SP, Rinckel LA, Garfinkel DJ (1998) A Ty1 integrase nuclear localization signal required for retrotransposition. Mol Cell Biol 18:1105–1114
Morillon A, Bénard L, Springer M, Lesage P (2002) Differential effects of chromatin and Gcn4 on the 50-fold range of expression among individual yeast Ty1 retrotransposons. Mol Cell Biol 22:2078–2088
Mularoni L, Zhou Y, Bowen T, Gangadharan S, Wheelan SJ, Boeke JD (2012) Retrotransposon Ty1 integration targets specifically positioned asymmetric nucleosomal DNA segments in tRNA hotspots. Genome Res 22:693–703. doi:10.1101/gr.129460.111
Murcia PR, Arnaud F, Palmarini M (2007) The transdominant endogenous retrovirus enJS56A1 associates with and blocks intracellular trafficking of Jaagsiekte sheep retrovirus Gag. J Virol 81:1762–1772. doi:10.1128/JVI.01859-06
Nishida Y, Pachulska-Wieczorek K, Blaszczyk L, Saha A, Gumna J, Garfinkel DJ, Purzycka KJ (2015) Ty1 retrovirus-like element Gag contains overlapping restriction factor and nucleic acid chaperone functions. Nucleic Acid Res 43:7414–7431. doi:10.1093/nar/gkv695
Palmer KJ, Tichelaar W, Myers N, Burns NR, Butcher SJ, Kingsman AJ, Fuller SD, Saibil HR (1997) Cryo-electron microscopy structure of yeast Ty retrotransposon virus-like particles. J Virol 71:6863–6868
Parker R (2012) RNA degradation in Saccharomyces cerevisiae. Genetics 191:671–702. doi:10.1534/genetics.111.137265
Peterson-Burch BD, Voytas DF (2002) Genes of the Pseudoviridae (Ty1/copia retrotransposons). Mol Biol Evol 19:1832–1845
Purzycka KJ, Legiewicz M, Matsuda E, Eizentstat LD, Lusvarghi S, Saha A, Le Grice SF, Garfinkel DJ (2013) Exploring Ty1 retrotransposon RNA structure within virus-like particles. Nucleic Acid Res 41:463–473. doi:10.1093/nar/gks983
Qi CF, Bonhomme F, Buckler-White A, Buckler C, Orth A, Lander MR, Chattopadhyay SK, Morse HC (1998) Molecular phylogeny of Fv1. Mamm Genome 9:1049–1055
Rihn SJ, Wilson SJ, Loman NJ, Alim M, Bakker SE, Bhella D, Gifford RJ, Rixon FJ, Bieniasz PD (2013) Extreme genetic fragility of the HIV-1 capsid. PLoS Pathog 9:e1003461. doi:10.1371/journal.ppat.1003461
Saha A, Mitchell JA, Nishida Y, Hildreth JE, Ariberre JA, Gilbert WV, Garfinkel DJ (2015) A trans-dominant form of Gag restricts Ty1 retrotransposition and mediates copy number control. J Virol 89:3922–3938. doi:10.1128/JVI.03060-14
Schulte B, Buffone C, Opp S, Di Nunzio F, De Souza Augusto, Aranha Vieira D, Brandariz-Nunez A, Diaz-Griffero F (2015) Restriction of HIV-1 requires the N-terminal region of MxB/Mx2 as a capsid-binding motif but not as a nuclear localization signal. J Virol. doi:10.1128/JVI.00753-15
Servant G, Pinson B, Tchalikian-Cosson A, Coulpier F, Lemoine S, Pennetier C, Bridier-Nahmias A, Todeschini A-L, Fayol H, Daignan-Fornier B, Lesage P (2012) Tye7 regulates yeast Ty1 retrotransposon sense and antisense transcription in response to adenylic nucleotides stress. Nucleic Acid Res 40:5271–5282. doi:10.1093/nar/gks166
Simons RW, Kleckner N (1983) Translational control of IS10 transposition. Cell 34:683–691
Soll SJ, Wilson SJ, Kutluay SB, Hatziioannou T, Bieniasz PD (2013) Assisted evolution enables HIV-1 to overcome a high TRIM5alpha-imposed genetic barrier to rhesus macaque tropism. PLoS Pathog 9:e1003667. doi:10.1371/journal.ppat.1003667
Suzuki K, Morimoto M, Kondo C, Ohsumi Y (2011) Selective autophagy regulates insertional mutagenesis by the Ty1 retrotransposon in Saccharomyces cerevisiae. Dev Cell 21:358–365. doi:10.1016/j.devcel.2011.06.023
Tekeste SS, Wilkinson TA, Weiner EM, Xu X, Miller JT, Le Grice SFJ, Clubb RT, Chow SA (2015) Interaction between reverse transcriptase and integrase is required for reverse transcription during HIV-1 replication. J Virol 89:12058–12069
Tucker JM, Larango ME, Wachsmuth LP, Kannan N, Garfinkel DJ (2015) The Ty1 retrotransposon restriction factor p22 targets Gag. PLoS Genet 11:e1005571. doi:10.1371/journal.pgen.1005571
VanHoute D, Maxwell PH (2014) Extension of Saccharomyces paradoxus chronological lifespan by retrotransposons in certain media conditions is associated with changes in reactive oxygen species. Genetics 198:531–545. doi:10.1534/genetics.114.168799
Wilhelm M, Wilhelm F-X (2006) Cooperation between reverse transcriptase and integrase during reverse transcription and formation of the preintegrative complex of Ty1. Eukaryot Cell 5:1760–1769. doi:10.1128/EC.00159-06
Winston F, Durbin KJ, Fink GR (1984) The SPT3 gene is required for normal transcription of Ty elements in S. cerevisiae. Cell 39:675–682
Zheng YH, Jeang KT, Tokunaga K (2012) Host restriction factors in retroviral infection: promises in virus-host interaction. Retrovirology 9:112. doi:10.1186/1742-4690-9-112
Zhu K, Dobard C, Chow SA (2004) Requirement for integrase during reverse transcription of human immunodeficiency virus type 1 and the effect of cysteine mutations of integrase on its interactions with reverse transcriptase. J Virol 78:5045–5055
Acknowledgments
This work was supported by the National Science Center, Poland [2011/01/D/NZ1/03478, 2012/06/A/ST6/00384]; Foundation for Polish Science [HOMING PLUS/2012-6/12 to K.J.P.]; Ministry of Science and Higher Education, Poland [0492/IP1/2013/72 to K.J.P.]; National Institutes of Health [GM095622 to D.J.G.]; National Science Foundation Graduate Fellowship [1011RH25213 to J.M.T.]; and the University of Georgia Research Foundation [to D.J.G.]. We also thank Wioletta Czaja for helpful comments.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by M. Kupiec.
Rights and permissions
About this article
Cite this article
Garfinkel, D.J., Tucker, J.M., Saha, A. et al. A self-encoded capsid derivative restricts Ty1 retrotransposition in Saccharomyces . Curr Genet 62, 321–329 (2016). https://doi.org/10.1007/s00294-015-0550-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00294-015-0550-6