Cited by 180RNA and protein synthesis mechanismsRedox biology and oxidative stressGenomics and Phylogenetic Studies

Peroxisomal lactate dehydrogenase is generated by translational readthrough in mammals

Open access
Schueren, Fabian, Lingner, Thomas, George, Rosemol, Hofhuis, Julia, Dickel, Corinna, Gärtner, Jutta, Thoms, Sven·2014·eLife

Abstract

Translational readthrough gives rise to low abundance proteins with C-terminal extensions beyond the stop codon. To identify functional translational readthrough, we estimated the readthrough propensity (RTP) of all stop codon contexts of the human genome by a new regression model in silico, identified a nucleotide consensus motif for high RTP by using this model, and analyzed all readthrough extensions in silico with a new predictor for peroxisomal targeting signal type 1 (PTS1). Lactate dehydrogenase B (LDHB) showed the highest combined RTP and PTS1 probability. Experimentally we show that at least 1.6% of the total cellular LDHB is targeted to the peroxisome by a conserved hidden PTS1. The readthrough-extended lactate dehydrogenase subunit LDHBx can also co-import LDHA, the other LDH subunit, into peroxisomes. Peroxisomal LDH is conserved in mammals and likely contributes to redox equivalent regeneration in peroxisomes.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.7554/elife.03640

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 59

  1. Baranov PV Gesteland RF Atkins JF 2002 Recoding: translational bifurcations in gene expression Gene 286 187 201 10.1016/S0378-1119(02)00423-7 11943474 · DOI
  2. Baumgart E Fahimi HD Stich A Völkl A 1996 L-lactate dehydrogenase A4- and A3B isoforms are bona fide peroxisomal enzymes in rat liver. Evidence for involvement in intraperoxisomal NADH reoxidation The Journal of Biological Chemistry 271 3846 3855 10.1074/jbc.271.7.3846 8632003 · DOI
  3. Beier H Grimm M 2001 Misreading of termination codons in eukaryotes by natural nonsense suppressor tRNAs Nucleic Acids Research 29 4767 4782 10.1093/nar/29.23.4767 11726686 PMC96686 · DOI
  4. Bidou L Allamand V Rousset JP Namy O 2012 Sense from nonsense: therapies for premature stop codon diseases Trends in Molecular Medicine 18 679 688 10.1016/j.molmed.2012.09.008 23083810 · DOI
  5. Boyer SH Fainer DC Watson-Williams EJ 1963 Lactate dehydrogenase variant from human blood: evidence for molecular subunits Science 141 642 643 10.1126/science.141.3581.642 14014718 · DOI
  6. Braverman NE D'Agostino MD Maclean GE 2013 Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives Developmental Disabilities Research Reviews 17 187 196 10.1002/ddrr.1113 23798008 · DOI
  7. Brocard C Hartig A 2006 Peroxisome targeting signal 1: is it really a simple tripeptide? Biochimica et Biophysica Acta 1763 1565 1573 10.1016/j.bbamcr.2006.08.022 17007944 · DOI
  8. Brooks GA 2009 Cell-cell and intracellular lactate shuttles The Journal of Physiology 587 5591 5600 10.1113/jphysiol.2009.178350 19805739 PMC2805372 · DOI
  9. Chittum HS Lane WS Carlson BA Roller PP Lung FD Lee BJ Hatfield DL 1998 Rabbit beta-globin is extended beyond its UGA stop codon by multiple suppressions and translational reading gaps Biochemistry 37 10866 10870 10.1021/bi981042r 9692979 · DOI
  10. Dunn JG Foo CK Belletier NG Gavis ER Weissman JS 2013 Ribosome profiling reveals pervasive and regulated stop codon readthrough in Drosophila melanogaster eLife 2 e01179 10.7554/eLife.01179 24302569 PMC3840789 · DOI
  11. Eswarappa SM Potdar AA Koch WJ Fan Y Vasu K Lindner D Willard B Graham LM DiCorleto PE Fox PL 2014 Programmed translational readthrough generates antiangiogenic VEGF-Ax Cell 157 1605 1618 10.1016/j.cell.2014.04.033 24949972 PMC4113015 · DOI
  12. Firth AE Brierley I 2012 Non-canonical translation in RNA viruses The Journal of General Virology 93 1385 1409 10.1099/vir.0.042499-0 22535777 PMC3542737 · DOI
  13. Firth AE Wills NM Gesteland RF Atkins JF 2011 Stimulation of stop codon readthrough: frequent presence of an extended 3′ RNA structural element Nucleic Acids Research 39 6679 6691 10.1093/nar/gkr224 21525127 PMC3159437 · DOI
  14. Flicek P Ahmed I Amode MR Barrell D Beal K Brent S Carvalho-Silva D Clapham P Coates G Fairley S Fitzgerald S Gil L Garcia-Giron C Gordon L Hourlier T Hunt S Juettemann T Kahari AK Keenan S Komorowska M Kulesha E Longden I Maurel T McLaren WM Muffato M Nag R Overduin B Pignatelli M Pritchard B Pritchard E Riat HS Ritchie GR Ruffier M Schuster M Sheppard D Sobral D Taylor K Thormann A Trevanion S White S Wilder SP Aken BL Birney E Cunningham F Dunham I Harrow J Herrero J Hubbard TJ Johnson N Kinsella R Parker A Spudich G Yates A Zadissa A Searle SM 2012 Ensembl 2013 Nucleic Acids Research 41 D48 D55 10.1093/nar/gks1236 23203987 PMC3531136 · DOI
  15. Floquet C Hatin I Rousset JP Bidou L 2012 Statistical analysis of readthrough levels for nonsense mutations in mammalian cells reveals a major determinant of response to gentamicin PLOS Genetics 8 e1002608 10.1371/journal.pgen.1002608 22479203 PMC3315467 · DOI
  16. Freitag J Ast J Bölker M 2012 Cryptic peroxisomal targeting via alternative splicing and stop codon read-through in fungi Nature 485 522 525 10.1038/nature11051 22622582 · DOI
  17. Geller AI Rich A 1980 A UGA termination suppression tRNATrp active in rabbit reticulocytes Nature 283 41 46 10.1038/283041a0 7350525 · DOI
  18. Gladden LB 2004 Lactate metabolism: a new paradigm for the third millennium The Journal of Physiology 558 5 30 10.1113/jphysiol.2003.058701 15131240 PMC1664920 · DOI
  19. Goldberg E Eddy EM Duan C Odet F 2009 LDHC: the ultimate testis-specific gene Journal of Andrology 31 86 94 10.2164/jandrol.109.008367 19875487 PMC2915756 · DOI · Paper page
  20. Gronemeyer T Wiese S Ofman R Bunse C Pawlas M Hayen H Eisenacher M Stephan C Meyer HE Waterham HR Erdmann R Wanders RJ Warscheid B 2013 The proteome of human liver peroxisomes: identification of five new peroxisomal constituents by a label-free quantitative proteomics survey PLOS ONE 8 e57395 10.1371/journal.pone.0057395 23460848 PMC3583843 · DOI
  21. Gualdrón-López M Brennand A Hannaert V Quiñones W Cáceres AJ Bringaud F Concepción JL Michels PAM 2012 When, how and why glycolysis became compartmentalised in the Kinetoplastea. A new look at an ancient organelle International Journal for Parasitology 42 1 20 10.1016/j.ijpara.2011.10.007 22142562 · DOI
  22. Harrell L Melcher U Atkins JF 2002 Predominance of six different hexanucleotide recoding signals 3′ of read-through stop codons Nucleic Acids Research 30 2011 2017 10.1093/nar/30.9.2011 11972340 PMC113845 · DOI
  23. Hoerl AE Kennard RW 1970 Ridge regression: biased estimation for nonorthogonal problems Technometrics 12 55 67 10.1080/00401706.1970.10488634 · DOI · Paper page
  24. Jungreis I Lin MF Spokony R Chan CS Negre N Victorsen A White KP Kellis M 2011 Evidence of abundant stop codon readthrough in Drosophila and other metazoa Genome Research 21 2096 2113 10.1101/gr.119974.110 21994247 PMC3227100 · DOI
  25. Keeling KM Xue X Gunn G Bedwell DM 2014 Therapeutics based on stop codon readthrough Annual Review of Genomics and Human Genetics 15 371 394 10.1146/annurev-genom-091212-153527 PMC5304456 24773318 · DOI · Paper page
  26. Krogh A Larsson B von Heijne G Sonnhammer EL 2001 Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes Journal of Molecular Biology 305 567 580 10.1006/jmbi.2000.4315 11152613 · DOI · Paper page
  27. Kunze M Hartig A 2013 Permeability of the peroxisomal membrane: lessons from the glyoxylate cycle Frontiers in Physiology 4 204 10.3389/fphys.2013.00204 23966945 PMC3743077 · DOI
  28. Lanyon-Hogg T Warriner SL Baker A 2010 Getting a camel through the eye of a needle: the import of folded proteins by peroxisomes Biology of the cell/under the auspices of the European Cell Biology Organization 102 245 263 10.1042/BC20090159 20146669 · DOI
  29. Li G Rice CM 1993 The signal for translational readthrough of a UGA codon in Sindbis virus RNA involves a single cytidine residue immediately downstream of the termination codon Journal of Virology 67 5062 5067 8331741 PMC237898
  30. Lin MF Jungreis I Kellis M 2011 PhyloCSF: a comparative genomics method to distinguish protein coding and non-coding regions Bioinformatics 27 i275 i282 10.1093/bioinformatics/btr209 21685081 PMC3117341 · DOI
  31. Lingner T Kataya AR Antonicelli GE Benichou A Nilssen K Chen XY Siemsen T Morgenstern B Meinicke P Reumann S 2011 Identification of novel plant peroxisomal targeting signals by a combination of machine learning methods and in vivo subcellular targeting analyses The Plant Cell 23 1556 1572 10.1105/tpc.111.084095 21487095 PMC3101550 · DOI
  32. Lodhi IJ Semenkovich CF 2014 Peroxisomes: a nexus for lipid metabolism and cellular signaling Cell Metabolism 19 380 392 10.1016/j.cmet.2014.01.002 24508507 PMC3951609 · DOI · Paper page
  33. Loughran G Chou MY Ivanov IP Jungreis I Kellis M Kiran AM Baranov PV Atkins JF 2014 Evidence of efficient stop codon readthrough in four mammalian genes Nucleic Acids Research 42 8928 8938 10.1093/nar/gku608 25013167 PMC4132726 · DOI
  34. Markert CL 1963 Lactate dehydrogenase isozymes: dissociation and recombination of subunits Science 140 1329 1330 10.1126/science.140.3573.1329 17802174 · DOI
  35. Maynard EL Gatto GJ Jnr Berg JM 2004 Pex5p binding affinities for canonical and noncanonical PTS1 peptides Proteins 55 856 861 10.1002/prot.20112 15146484 · DOI
  36. McCaughan KK Brown CM Dalphin ME Berry MJ Tate WP 1995 Translational termination efficiency in mammals is influenced by the base following the stop codon Proceedings of the National Academy of Sciences of USA 92 5431 5435 10.1073/pnas.92.12.5431 PMC41708 7777525 · DOI · Paper page
  37. McClelland GB Khanna S González GF Eric Butz C Brooks GA 2003 Peroxisomal membrane monocarboxylate transporters: evidence for a redox shuttle system? Biochemical and Biophysical Research Communications 304 130 135 10.1016/S0006-291X(03)00550-3 12705896 · DOI
  38. McGroarty E Hsieh B Wied DM Gee R Tolbert NE 1974 Alpha hydroxy acid oxidation by peroxisomes Archives of Biochemistry and Biophysics 161 194 210 10.1016/0003-9861(74)90251-3 · DOI
  39. McNew JA Goodman JM 1996 The targeting and assembly of peroxisomal proteins: some old rules do not apply Trends in Biochemical Sciences 21 54 58 10.1016/0968-0004(96)80866-8 8851661 · DOI
  40. Namy O Hatin I Rousset JP 2001 Impact of the six nucleotides downstream of the stop codon on translation termination EMBO Reports 2 787 793 10.1093/embo-reports/kve176 11520858 PMC1084031 · DOI
  41. Namy O Rousset JP Napthine S Brierley I 2004 Reprogrammed genetic decoding in cellular gene expression Molecular Cell 13 157 168 10.1016/S1097-2765(04)00031-0 14759362 · DOI · Paper page
  42. Osmundsen H 1982 Factors which can influence beta-oxidation by peroxisomes isolated from livers of clofibrate treated rats. Some properties of peroxisomal fractions isolated in a self-generated Percoll gradient by vertical rotor centrifugation The International Journal of Biochemistry 14 905 914 10.1016/0020-711X(82)90074-X 7128908 · DOI
  43. Pacho F Zambruno G Calabresi V Kiritsi D Schneider H 2011 Efficiency of translation termination in humans is highly dependent upon nucleotides in the neighbourhood of a (premature) termination codon Journal of Medical Genetics 48 640 644 10.1136/jmg.2011.089615 21693480 · DOI
  44. Read JA Winter VJ Eszes CM Sessions RB Brady RL 2001 Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase Proteins 43 175 185 10.1002/1097-0134(20010501)43:23.0.CO;2-# 11276087 · DOI
  45. Salido E Pey AL Rodriguez R Lorenzo V 2012 Primary hyperoxalurias: disorders of glyoxylate detoxification Biochimica et Biophysica Acta 1822 1453 1464 10.1016/j.bbadis.2012.03.004 22446032 · DOI
  46. Schueren F Lingner T George R Hofhuis J Dickel C Gärtner J Thoms S 2014 Data from: Peroxisomal lactate dehydrogenase is generated by translational readthrough in mammals Dryad Digital Repository 10.5061/dryad.j2n18 PMC4359377 25247702 · DOI
  47. Schwarz F Aebi M 2011 Mechanisms and principles of N-linked protein glycosylation Current Opinion in Structural Biology 21 576 582 10.1016/j.sbi.2011.08.005 21978957 · DOI
  48. Smith JJ Aitchison JD 2013 Peroxisomes take shape Nature Reviews Molecular Cell Biology 14 803 817 10.1038/nrm3700 PMC4060825 24263361 · DOI
  49. Stornaiuolo M Lotti LV Borgese N Torrisi MR Mottola G Martire G Bonatti S 2003 KDEL and KKXX retrieval signals appended to the same reporter protein determine different trafficking between endoplasmic reticulum, intermediate compartment, and Golgi complex Molecular Biology of the Cell 14 889 902 10.1091/mbc.E02-08-0468 12631711 PMC151567 · DOI
  50. Thoms S Hofhuis J Thöing C Gärtner J Niemann HH 2011 The unusual extended C-terminal helix of the peroxisomal α/β-hydrolase Lpx1 is involved in dimer contacts but dispensable for dimerization Journal of Structural Biology 175 362 371 10.1016/j.jsb.2011.06.008 21741480 · DOI
  51. Tuite MF Cox BS 2003 Propagation of yeast prions Nature Reviews Molecular Cell Biology 4 878 890 10.1038/nrm1247 14625537 · DOI
  52. Visser WF van Roermund CWT Ijlst L Waterham HR Wanders RJ 2007 Metabolite transport across the peroxisomal membrane The Biochemical Journal 401 365 375 10.1042/BJ20061352 17173541 PMC1820816 · DOI
  53. Völkl A Fahimi HD 1985 Isolation and characterization of peroxisomes from the liver of normal untreated rats European Journal of Biochemistry 149 257 265 10.1111/j.1432-1033.1985.tb08920.x 3996409 · DOI
  54. Waterhouse AM Procter JB Martin DM Clamp M Barton GJ 2009 Jalview Version 2–a multiple sequence alignment editor and analysis workbench Bioinformatics 25 1189 1191 10.1093/bioinformatics/btp033 19151095 PMC2672624 · DOI
  55. Workman CT Yin Y Corcoran DL Ideker T Stormo GD Benos PV 2005 enoLOGOS: a versatile web tool for energy normalized sequence logos Nucleic Acids Research 33 W389 W392 10.1093/nar/gki439 15980495 PMC1160200 · DOI
  56. Yamaguchi Y Hayashi A Campagnoni CW Kimura A Inuzuka T Baba H 2012 L-mpz, a novel isoform of myelin P0, is produced by stop codon readthrough The Journal of Biological Chemistry 287 17765 17776 10.1074/jbc.M111.314468 22457349 PMC3366853 · DOI
  57. Zerangue N Malan MJ Fried SR Dazin PF Jan YN Jan LY Schwappach B 2001 Analysis of endoplasmic reticulum trafficking signals by combinatorial screening in mammalian cells Proceedings of the National Academy of Sciences of USA 98 2431 2436 10.1073/pnas.051630198 PMC30155 11226256 · DOI
  58. Zhang FL Casey PJ 1996 Protein prenylation: molecular mechanisms and functional consequences Annual Review of Biochemistry 65 241 269 10.1146/annurev.bi.65.070196.001325 8811180 · DOI
  59. Zielinska DF Gnad F Wiśniewski JR Mann M 2010 Precision mapping of an in vivo N-glycoproteome reveals rigid topological and sequence constraints Cell 141 897 907 10.1016/j.cell.2010.04.012 20510933 · DOI

Cited by

Sorted by citations

Authors
Schueren, F., Lingner, T., George, R., Hofhuis, J., Dickel, C., Gärtner, J., & Thoms, S.
Affiliations
  • Universitätsmedizin Göttingen (DE)
  • University of Göttingen (DE)
Corresponding author
Thoms, Sven
Venue
eLife
Published
2014-09-23
Volume
3
Pages
e03640-e03640
ISSN
2050-084X (ISSN-L)
OpenAlex
W2155346577
Cited by
180
References
2
Citations by year
2026: 9 · 2025: 11 · 2024: 17 · 2023: 9 · 2022: 23 · 2021: 16 · 2020: 20 · 2019: 16 · 2018: 12 · 2017: 11 · 2016: 18 · 2015: 18
FWCI
5.91
Type
journal article
Language
en
Open access
Locations
  • eLife (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
  • GRO (submittedVersion, cc-by)
Funders
  • Georg-August-Universität Göttingen (Research Program, Faculty of Medicine,)
  • Deutsche Forschungsgemeinschaft (LI2050/1-1, GA354/7-1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
Keywords
translational readthrough, LDHB, LDHA, peroxisome targeting, peroxisome biogenesis
MeSH terms
Animals, Base Sequence, Cell Line, Computer Simulation, Humans, Isoenzymes, L-Lactate Dehydrogenase, Mammals, Molecular Sequence Data, Protein Biosynthesis, Genome, Conserved Sequence, Genes, Reporter, Codon, Terminator, Peroxisomes, Protein Transport, Protein Sorting Signals, Rats

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review