CoChat
Sign Up
Cited by 54

Human angiogenin is a potent cytotoxin in the absence of ribonuclease inhibitor

Thomas, Sydney P., Hoang, Trish T., Ressler, Valerie T., Raines, Ronald T.·2018·RNA
DOI 10.1261/rna.065516.117PMC PMC6049508
Open this paper in CoChat — free account

Abstract

Angiogenin (ANG) is a secretory ribonuclease that promotes the proliferation of endothelial cells, leading to angiogenesis. This function relies on its ribonucleolytic activity, which is low for simple RNA substrates. Upon entry into the cytosol, ANG is sequestered by the ribonuclease inhibitor protein (RNH1). We find that ANG is a potent cytotoxin for RNH1-knockout HeLa cells, belying its inefficiency as a nonspecific catalyst. The toxicity does, however, rely on the ribonucleolytic activity of ANG and a cytosolic localization, which lead to the accumulation of particular tRNA fragments (tRFs), such as tRF-5 Gly-GCC. These up-regulated tRFs are highly cytotoxic at physiological concentrations. Although ANG is well-known for its promotion of cell growth, our results reveal that ANG can also cause cell death.

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 · 10.1261/rna.065516.117

Cites

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?

  • The abundance of specific tRFs correlates with the levels of functional angiogenin in the cell.

    “Since the abundance of these specific fragments has been shown to correlate with the levels of functional angiogenin in the cell (54)”

    From A mouse tissue atlas of small noncoding RNA (2020) · cites this paper as [54]

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

No references could be resolved yet.

Research works printed but not linked: 65

  1. Backes C, Khaleeq QT, Meese E, Keller A. 2016 miEAA: microRNA enrichment analysis and annotation. Nucleic Acids Res 44: W110– W116. 27131362 PMC4987907
  2. Badet J. 1999 Angiogenin, a potent mediator of angiogenesis. Biological, biochemical and structural properties. Pathol Biol (Paris) 47: 345– 351. 10372403
  3. Bailey TL. 2011 DREME: motif discovery in transcription factor ChIP-seq data. Bioinformatics 27: 1653– 1659. 21543442 PMC3106199
  4. Bárcena C, Stefanovic M, Tutusaus A, Martinez-Nieto GA, Martinez L, García-Ruiz C, de Mingo A, Caballeria J, Fernandez-Checa JC, Marí M, 2015 Angiogenin secretion from hepatoma cells activates hepatic stellate cells to amplify a self-sustained cycle promoting liver cancer. Sci Rep 5: 7916. 25604905 PMC4300499
  5. Blanco S, Dietmann S, Flores JV, Hussain S, Kutter C, Humphreys P, Lukk M, Lombard P, Treps L, Popis M, 2014 Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders. EMBO J 33: 2020– 2039. 25063673 PMC4195770
  6. Blázquez M, Fominaya JM, Hofsteenge J. 1996 Oxidation of sulfhydryl groups of ribonuclease inhibitor in epithelial cells is sufficient for its intracellular degradation. J Biol Chem 271: 18638– 18642. 8702516
  7. Chao TY, Raines RT. 2013 Fluorogenic label to quantify the cytosolic delivery of macromolecules. Mol Biosyst 9: 339– 342. 23340874 PMC3588161
  8. de Hoon MJ, Imoto S, Nolan J, Miyano S. 2004 Open source clustering software. Bioinformatics 20: 1453– 1454. 14871861
  9. Deng J, Ptashkin RN, Chen Y, Cheng Z, Liu G, Phan T, Deng X, Zhou J, Lee I, Lee YS, 2015 Respiratory syncytial virus utilizes a tRNA fragment to suppress antiviral responses through a novel targeting mechanism. Mol Ther 23: 1622– 1629. 26156244 PMC4817927
  10. Dickson KA, Haigis MC, Raines RT. 2005 Ribonuclease inhibitor: Structure and function. Prog Nucleic Acid Res Mol Biol 80: 349– 374. 16164979 PMC2811166
  11. Eller CH, Lomax JE, Raines RT. 2014 Bovine brain ribonuclease is the functional homolog of human ribonuclease 1. J Biol Chem 289: 25996– 26006. 25078100 PMC4176206
  12. Emara MM, Ivanov P, Hickman T, Dawra N, Tisdale S, Kedersha N, Hu Gf, Anderson P. 2010 Angiogenin-induced tRNA-derived stress-induced RNAs promote stress-induced stress granule assembly. J Biol Chem 285: 10959– 10968. 20129916 PMC2856301
  13. Fett JW, Strydom DJ, Lobb RR, Alderman EM, Bethune JL, Riordan JF, Vallee BL. 1985 Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells. Biochemistry 24: 5480– 5486. 4074709
  14. Fominaya JM, Hofsteenge J. 1992 Inactivation of ribonuclease inhibitor by thiol–disulfide exchange. J Biol Chem 267: 24655– 24660. 1447207
  15. Haigis MC, Raines RT. 2003 Secretory ribonucleases are internalized by a dynamin-independent endocytic pathway. J Cell Sci 116: 313– 324. 12482917 PMC2812863
  16. Haigis MC, Kurten EL, Raines RT. 2003 Ribonuclease inhibitor as an intracellular sentry. Nucleic Acids Res 31: 1024– 1032. 12560499 PMC149185
  17. Hoang TT, Raines RT. 2017 Molecular basis for the autonomous promotion of cell proliferation by angiogenin. Nucleic Acids Res 45: 818– 831. 27915233 PMC5314776
  18. Hu Gf. 1998 Neomycin inhibits angiogenin-induced angiogenesis. Proc Natl Acad Sci 95: 9791– 9795. 9707554 PMC21415
  19. Hu GF, Strydom DJ, Fett JW, Riordan JF, Vallee BL. 1993 Actin is a binding protein for angiogenin. Proc Natl Acad Sci 90: 1217– 1221. 7679494 PMC45843
  20. Hu Gf, Riordan JF, Vallee BL. 1997 A putative angiogenin receptor in angiogenin-responsive human endothelial cells. Proc Natl Acad Sci 94: 2204– 2209. 9122172 PMC20065
  21. Ivanov P, Emara MM, Villen J, Gygi SP, Anderson P. 2011 Angiogenin-induced tRNA fragments inhibit translation initiation. Mol Cell 43: 613– 623. 21855800 PMC3160621
  22. Ivanov P, O'Day E, Emara MM, Wagner G, Lieberman J, Anderson P. 2014 G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments. Proc Natl Acad Sci 111: 18201– 18206. 25404306 PMC4280610
  23. Kieran D, Sebastia J, Greenway MJ, King MA, Connaughton D, Concannon CG, Fenner B, Hardiman O, Prehn JH. 2008 Control of motoneuron survival by angiogenin. J Neurosci 28: 14056– 14061. 19109488 PMC6671464
  24. Kikin O, D'Antonio L, Bagga PS. 2006 QGRS Mapper: a web-based server for predicting G-quadruplexes in nucleotide sequences. Nucleic Acids Res 34: W676– W682. 16845096 PMC1538864
  25. Kim BM, Schultz LW, Raines RT. 1999 Variants of ribonuclease inhibitor that resist oxidation. Protein Sci 8: 430– 434. 10048337 PMC2144251
  26. Lee FS, Shapiro R, Vallee BL. 1989 Tight-binding inhibition of angiogenin and ribonuclease A by placental ribonuclease inhibitor. Biochemistry 28: 225– 230. 2706246
  27. Leland PA, Staniszewski KE, Park C, Kelemen BR, Raines RT. 2002 The ribonucleolytic activity of angiogenin. Biochemistry 41: 1343– 1350. 11802736
  28. Li S, Hu GF. 2012 Emerging role of angiogenin in stress response and cell survival under adverse conditions. J Cell Physiol 227: 2822– 2826. 22021078 PMC3271170
  29. Li Q, Hu B, Hu Gw, Chen Cy, Niu X, Liu J, Zhou Sm, Zhang C1, Wang Y, Deng ZF. 2016 tRNA-derived small non-coding RNAs in response to ischemia inhibit angiogenesis. Sci Rep 6: 20850. 26865164 PMC4749989
  30. Lixin R, Efthymiadis A, Henderson B, Jans DA. 2001 Novel properties of the nucleolar targeting signal of human angiogenin. Biochem Biophys Res Commun 284: 185– 193. 11374889
  31. Lomax JE, Eller CH, Raines RT. 2012 Rational design and evaluation of mammalian ribonuclease cytotoxins. Methods Enzymol 502: 273– 290. 22208989 PMC3304445
  32. Lyons SM, Achorn C, Kedersha NL, Anderson PJ, Ivanov P. 2016 YB-1 regulates tiRNA-induced stress granule formation but not translational repression. Nucleic Acids Res 44: 6949– 6960. 27174937 PMC5001593
  33. Lyons SM, Fay MM, Akiyama Y, Anderson PJ, Ivanov P. 2017 RNA biology of angiogenin: current state and perspectives. RNA Biol 14: 171– 178. 28010172 PMC5324756
  34. Moroianu J, Riordan JF. 1994 Nuclear translocation of angiogenin in proliferating endothelial cells is essential to its angiogenic activity. Proc Natl Acad Sci 91: 1677– 1681. 8127865 PMC43226
  35. Okamura K. 2012 Diversity of animal small RNA pathways and their biological utility. Wiley Interdiscip Rev RNA 3: 351– 368. 22086843
  36. Olvedy M, Scaravilli M, Hoogstrate Y, Visakorpi T, Jenster G, Martens-Uzunova ES. 2016 A comprehensive repertoire of tRNA-derived fragments in prostate cancer. Oncotarget 7: 24766– 24777. 27015120 PMC5029740
  37. Panero R, Rinaldi A, Memoli D, Nassa G, Ravo M, Rizzo F, Tarallo R, Milanesi L, Weisz A, Giurato G. 2017 iSmaRT: A toolkit for a comprehensive analysis of small RNA-seq data. Bioinformatics 33: 938– 940. 28057684
  38. Papageorgiou AC, Shapiro R, Acharya KR. 1997 Molecular recognition of human angiogenin by placental ribonuclease inhibitor—an X-ray crystallographic study at 2.0 Å resolution. EMBO J 16: 5162– 5177. 9311977 PMC1170149
  39. Pizzo E, Sarcinelli C, Sheng J, Fusco S, Formiggini F, Netti P, Yu W, D'Alessio G, Hu Gf. 2013 Ribonuclease/angiogenin inhibitor 1 regulates stress-induced subcellular localization of angiogenin to control growth and survival. J Cell Sci 126: 4308– 4319. 23843625 PMC3772394
  40. Riordan JF. 2001 Angiogenin. Methods Enzymol 341: 263– 273. 11582782
  41. Rueda A, Barturen G, Lebron R, Gomez-Martin C, Alganza A, Oliver JL, Hackenberg M. 2015 sRNAtoolbox: an integrated collection of small RNA research tools. Nucleic Acids Res 43: W467– W473. 26019179 PMC4489306
  42. Rutkoski TJ, Kurten EL, Mitchell JC, Raines RT. 2005 Disruption of shape-complementarity markers to create cytotoxic variants of ribonuclease A. J Mol Biol 354: 41– 54. 16188273
  43. Saikia M, Hatzoglou M. 2015 The many virtues of tRNA-derived stress-induced RNAs (tiRNAs): discovering novel mechanisms of stress response and effect on human health. J Biol Chem 290: 29761– 29768. 26463210 PMC4705977
  44. Saikia M, Krokowski D, Guan BJ, Ivanov P, Parisien M, Hu Gf, Anderson P, Pan T, Hatzoglou M. 2012a Genome-wide identification and quantitative analysis of cleaved tRNA fragments induced by cellular stress. J Biol Chem 287: 42708– 42725. 23086926 PMC3522271
  45. Saikia M, Krokowski D, Guan BJ, Ivanov P, Parisien M, Hu Gf, Anderson P, Pan T, Hatzoglou M. 2012b Genome-wide identification and quantitative analysis of cleaved tRNA fragments induced by cellular stress. J Biol Chem 287: 42708– 42725. 23086926 PMC3522271
  46. Saldanha AJ. 2004 Java Treeview—extensible visualization of microarray data. Bioinformatics 20: 3246– 3248. 15180930
  47. Saxena SK, Rybak SM, Davey RT Jr, Youle RJ, Ackerman EJ. 1992 Angiogenin is a cytotoxic, tRNA-specific ribonuclease in the RNase A superfamily. J Biol Chem 267: 21982– 21986. 1400510
  48. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. 2003 Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13: 2498– 2504. 14597658 PMC403769
  49. Shapiro R, Vallee BL. 1989 Site-directed mutagenesis of histidine-13 and histidine-114 of human angiogenin. Alanine derivatives inhibit angiogenin-induced angiogenesis. Biochemistry 28: 7401– 7408. 2479414
  50. Sharma U, Conine CC, Shea JM, Boskovic A, Derr AG, Bing XY, Belleannee C, Kucukural A, Serra RW, Sun F, 2016 Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351: 391– 396. 26721685 PMC4888079
  51. Sheng J, Xu Z. 2016 Three decades of research on angiogenin: a review and perspective. Acta Biochim Biophys Sin 48: 399– 410. 26705141 PMC4888354
  52. Skorupa A, King MA, Aparicio IM, Dussmann H, Coughlan K, Breen B, Kieran D, Concannon CG, Marin P, Prehn JH. 2012 Motoneurons secrete angiogenin to induce RNA cleavage in astroglia. J Neurosci 32: 5024– 5038. 22496549 PMC6622103
  53. Smith BD, Raines RT. 2006 Genetic selection for critical residues in ribonucleases. J Mol Biol 362: 459– 478. 16920150
  54. Sorrentino S. 2010 The eight human “canonical” ribonucleases: molecular diversity, catalytic properties, and special biological actions of the enzyme proteins. FEBS Lett 584: 2194– 2200. 20388512
  55. Sorrentino S, Libonati M. 1994 Human pancreatic-type and nonpancreatic-type ribonucleases: a direct side-by-side comparison of their catalytic properties. Arch Biochem Biophys 312: 340– 348. 8037446
  56. Sundlass NK, Eller CH, Cui Q, Raines RT. 2013 Contribution of electrostatics to the binding of pancreatic-type ribonucleases to membranes. Biochemistry 52: 6304– 6312. 23947917 PMC3839965
  57. Supek F, Bosnjak M, Skunca N, Smuc T. 2011 REVIGO summarizes and visualizes long lists of gene ontology terms. PLoS One 6: e21800. 21789182 PMC3138752
  58. Tarazona S, Furio-Tari P, Turra D, Pietro AD, Nueda MJ, Ferrer A, Conesa A. 2015 Data quality aware analysis of differential expression in RNA-seq with NOISeq R/Bioc package. Nucleic Acids Res 43: e140. 26184878 PMC4666377
  59. Thomas SP, Kim E, Kim JS, Raines RT. 2016 Knockout of the ribonuclease inhibitor gene leaves human cells vulnerable to secretory ribonucleases. Biochemistry 55: 6359– 6362. 27806571 PMC5148631
  60. Wang Q, Lee I, Ren J, Ajay SS, Lee YS, Bao X. 2013 Identification and functional characterization of tRNA-derived RNA fragments (tRFs) in respiratory syncytial virus infection. Mol Ther 21: 368– 379. 23183536 PMC3594034
  61. Weng C, Dong H, Chen G, Zhai Y, Bai R, Hu H, Lu L, Xu Z. 2012 miR-409–3p inhibits HT1080 cell proliferation, vascularization and metastasis by targeting angiogenin. Cancer Lett 323: 171– 179. 22531314
  62. Wilusz JE. 2015 Removing roadblocks to deep sequencing of modified RNAs. Nat Methods 12: 821– 822. 26317237 PMC4568847
  63. Xu Zp, Tsuji T, Riordan JF, Hu Gf. 2003 Identification and characterization of an angiogenin-binding DNA sequence that stimulates luciferase reporter gene expression. Biochemistry 42: 121– 128. 12515546
  64. Yamasaki S, Ivanov P, Hu Gf, Anderson P. 2009 Angiogenin cleaves tRNA and promotes stress-induced translational repression. J Cell Biol 185: 35– 42. 19332886 PMC2700517
  65. Zheng LL, Xu WL, Liu S, Sun WJ, Li JH, Wu J, Yang JH, Qu LH. 2016 tRF2Cancer: a web server to detect tRNA-derived small RNA fragments (tRFs) and their expression in multiple cancers. Nucleic Acids Res 44: W185– W193. 27179031 PMC4987945

Cited by

Sorted by citations

Authors
Thomas, S. P., Hoang, T. T., Ressler, V. T., & Raines, R. T.
ORCID
Raines, Ronald T.
Venue
RNA
Publisher
Cold Spring Harbor Laboratory
Published
2018-05-10
Volume
24
Issue
8
Pages
1018-1027
ISSN
  • 1355-8382
  • 1469-9001
DOI
10.1261/rna.065516.117
PMC
PMC6049508
Cited by
54
References
0
Language
en
Funders
  • National Science Foundation
  • Advanced Opportunity
  • Graduate Research Scholar Fellowship and by Molecular Biosciences Training (T32 GM007215)
  • National Institutes of Health (R01 CA073808)
  • University of Wisconsin Carbone Cancer Center Flow Cytometry Laboratory (P30 CA014520)
  • University of Wisconsin–Madison Department of Biochemistry Endowment

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