Protein & Cell

, Volume 2, Issue 8, pp 612–619 | Cite as

The dual role of ubiquitin-like protein Urm1 as a protein modifier and sulfur carrier

  • Fengbin Wang
  • Meiruo Liu
  • Rui Qiu
  • Chaoneng Ji


The ubiquitin-related modifier Urm1 can be covalently conjugated to lysine residues of other proteins, such as yeast Ahp1 and human MOCS3, through a mechanism involving the E1-like protein Uba4 (MOCS3 in humans). Similar to ubiquitination, urmylation requires a thioester intermediate and forms isopeptide bonds between Urm1 and its substrates. In addition, the urmylation process can be significantly enhanced by oxidative stress. Recent findings have demonstrated that Urm1 also acts as a sulfur carrier in the thiolation of eukaryotic tRNA via a mechanism that requires the formation of a thiocarboxylated Urm1. This role is very similar to that of prokaryotic sulfur carriers such as MoaD and ThiS. Evidence strongly supports the hypothesis that Urm1 is the molecular fossil in the evolutionary link between prokaryotic sulfur carriers and eukaryotic ubiquitin-like proteins. In the present review, we discuss the dual role of Urm1 in protein and tRNA modification.


Urm1 system tRNA modification Ub-like protein modification 


  1. Abbink, T.E.M., and Berkhout, B. (2008). HIV-1 reverse transcription initiation: a potential target for novel antivirals? Virus Res 134, 4–18.CrossRefGoogle Scholar
  2. Agris, P.F. (2008). Bringing order to translation: the contributions of transfer RNA anticodon-domain modifications. EMBO Rep 9, 629–635.CrossRefGoogle Scholar
  3. Behrens, P., Brinkmann, U., and Wellmann, A. (2003). CSE1L/CAS: its role in proliferation and apoptosis. Apoptosis 8, 39–44.CrossRefGoogle Scholar
  4. Björk, G.R., Huang, B., Persson, O.P., and Byström, A.S. (2007). A conserved modified wobble nucleoside (mcm5s2U) in lysyl-tRNA is required for viability in yeast. RNA 13, 1245–1255.CrossRefGoogle Scholar
  5. Bordo, D., and Bork, P. (2002). The rhodanese/Cdc25 phosphatase superfamily. Sequence-structure-function relations. EMBO Rep 3, 741–746.CrossRefGoogle Scholar
  6. Ciechanover A., Heller H., Katzetzion R., Hershko A. (1981). Activation of the Heat-Stable Polypeptide of the Atp-Dependent Proteolytic System. Proc Natl Acad Sci U S A 78, 761–765.CrossRefGoogle Scholar
  7. Dewez, M., Bauer, F., Dieu, M., Raes, M., Vandenhaute, J., and Hermand, D. (2008). The conserved Wobble uridine tRNA thiolase Ctu1-Ctu2 is required to maintain genome integrity. Proc Natl Acad Sci U S A 105, 5459–5464.CrossRefGoogle Scholar
  8. Fichtner, L., Jablonowski, D., Schierhorn, A., Kitamoto, H.K., Stark, M.J.R., and Schaffrath, R. (2003). Elongator’s toxin-target (TOT) function is nuclear localization sequence dependent and suppressed by post-translational modification. Mol Microbiol 49, 1297–1307.CrossRefGoogle Scholar
  9. Furukawa, K., Mizushima, N., Noda, T., and Ohsumi, Y. (2000). A protein conjugation system in yeast with homology to biosynthetic enzyme reaction of prokaryotes. J Biol Chem 275, 7462–7465.CrossRefGoogle Scholar
  10. Goehring, A.S., Rivers, D.M., and Sprague, G.F. Jr. (2003a). Attachment of the ubiquitin-related protein Urm1p to the antioxidant protein Ahp1p. Eukaryot Cell 2, 930–936.CrossRefGoogle Scholar
  11. Goehring, A.S., Rivers, D.M., and Sprague, G.F. Jr. (2003b). Urmylation: a ubiquitin-like pathway that functions during invasive growth and budding in yeast. Mol Biol Cell 14, 4329–4341.CrossRefGoogle Scholar
  12. Haas, A.L., Warms, J.V.B., Hershko, A., and Rose, I.A. (1982). Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation. J Biol Chem 257, 2543–2548.Google Scholar
  13. Hershko, A., Ciechanover, A., and Varshavsky, A. (2000). The ubiquitin system. Nat Med 6, 1073–1081.CrossRefGoogle Scholar
  14. Hochstrasser, M. (2000). Evolution and function of ubiquitin-like protein-conjugation systems. Nat Cell Biol 2, E153–E157.CrossRefGoogle Scholar
  15. Hochstrasser, M. (2009). Origin and function of ubiquitin-like proteins. Nature 458, 422–429.CrossRefGoogle Scholar
  16. Huang, B., Lu, J., and Byström, A.S. (2008). A genome-wide screen identifies genes required for formation of the wobble nucleoside 5-methoxycarbonylmethyl-2-thiouridine in Saccharomyces cerevisiae. RNA 14, 2183–2194.CrossRefGoogle Scholar
  17. Humbard, M.A., Miranda, H.V., Lim, J.M., Krause, D.J., Pritz, J.R., Zhou, G.Y., Chen, S.X., Wells, L., and Maupin-Furlow, J.A. (2010). Ubiquitin-like small archaeal modifier proteins (SAMPs) in Haloferax volcanii. Nature 463, 54–60.CrossRefGoogle Scholar
  18. Isel, C., Lanchy, J.M., Le Grice, S.F.J., Ehresmann, C., Ehresmann, B., and Marquet, R. (1996). Specific initiation and switch to elongation of human immunodeficiency virus type 1 reverse transcription require the post-transcriptional modifications of primer tRNA3Lys. EMBO J 15, 917–924.Google Scholar
  19. Isel, C., Marquet, R., Keith, G., Ehresmann, C., and Ehresmann, B. (1993). Modified nucleotides of tRNA(3Lys) modulate primer/template loop-loop interaction in the initiation complex of HIV-1 reverse transcription. J Biol Chem 268, 25269–25272.Google Scholar
  20. Iyer, L.M., Burroughs, A.M., and Aravind, L. (2006). The prokaryotic antecedents of the ubiquitin-signaling system and the early evolution of ubiquitin-like beta-grasp domains. Genome Biol 7, R60.CrossRefGoogle Scholar
  21. Jeong, J.S., Kwon, S.J., Kang, S.W., Rhee, S.G., and Kim, K. (1999). Purification and characterization of a second type thioredoxin peroxidase (type II TPx) from Saccharomyces cerevisiae. Biochemistry 38, 776–783.CrossRefGoogle Scholar
  22. Johansson, M.J.O., Esberg, A., Huang, B., Björk, G.R., and Byström, A.S. (2008). Eukaryotic wobble uridine modifications promote a functionally redundant decoding system. Mol Cell Biol 28, 3301–3312.CrossRefGoogle Scholar
  23. Lake, M.W., Wuebbens, M.M., Rajagopalan, K.V., and Schindelin, H. (2001). Mechanism of ubiquitin activation revealed by the structure of a bacterial MoeB-MoaD complex. Nature 414, 325–329.CrossRefGoogle Scholar
  24. Lee, J., Spector, D., Godon, C., Labarre, J., and Toledano, M.B. (1999). A new antioxidant with alkyl hydroperoxide defense properties in yeast. J Biol Chem 274, 4537–4544.CrossRefGoogle Scholar
  25. Leidel, S., Pedrioli, P.G.A., Bucher, T., Brost, R., Costanzo, M., Schmidt, A., Aebersold, R., Boone, C., Hofmann, K., and Peter, M. (2009). Ubiquitin-related modifier Urm1 acts as a sulphur carrier in thiolation of eukaryotic transfer RNA. Nature 458, 228–232.CrossRefGoogle Scholar
  26. Ling, J.Q., and Söll, D. (2010). Severe oxidative stress induces protein mistranslation through impairment of an aminoacyl-tRNA synthetase editing site. Proc Natl Acad Sci U S A 107, 4028–4033.CrossRefGoogle Scholar
  27. Lu, J., Esberg, A., Huang, B., and Byström, A.S. (2008). Kluyveromyces lactis gamma-toxin, a ribonuclease that recognizes the anticodon stem loop of tRNA. Nucleic Acids Res 36, 1072–1080.CrossRefGoogle Scholar
  28. Lu, J., Huang, B., Esberg, A., Johansson, M.J.O., and Byström, A.S. (2005). The Kluyveromyces lactis gamma-toxin targets tRNA anticodons. RNA 11, 1648–1654.CrossRefGoogle Scholar
  29. Marelja, Z., Stöcklein, W., Nimtz, M., and Leimkühler, S. (2008). A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a sulfur donor for MOCS3, a protein involved in molybdenum cofactor biosynthesis. J Biol Chem 283, 25178–25185.CrossRefGoogle Scholar
  30. Miranda, H.V., Nembhard, N., Su, D., Hepowit, N., Krause, D.J., Pritz, J.R., Phillips, C., Söll, D., and Maupin-Furlow, J.A. (2011). E1- and ubiquitin-like proteins provide a direct link between protein conjugation and sulfur transfer in archaea. Proc Natl Acad Sci U S A 108, 4417–4422.CrossRefGoogle Scholar
  31. Mueller, E.G. (2006). Trafficking in persulfides: delivering sulfur in biosynthetic pathways. Nat Chem Biol 2, 185–194.CrossRefGoogle Scholar
  32. Nakai, Y., Nakai, M., and Hayashi, H. (2008). Thio-modification of yeast cytosolic tRNA requires a ubiquitin-related system that resembles bacterial sulfur transfer systems. J Biol Chem 283, 27469–27476.CrossRefGoogle Scholar
  33. Nakai, Y., Nakai, M., Hayashi, H., and Kagamiyama, H. (2001). Nuclear localization of yeast Nfs1p is required for cell survival. J Biol Chem 276, 8314–8320.CrossRefGoogle Scholar
  34. Nakai, Y., Umeda, N., Suzuki, T., Nakai, M., Hayashi, H., Watanabe, K., and Kagamiyama, H. (2004). Yeast Nfs1p is involved in thiomodification of both mitochondrial and cytoplasmic tRNAs. J Biol Chem 279, 12363–12368.CrossRefGoogle Scholar
  35. Netzer, N., Goodenbour, J.M., David, A., Dittmar, K.A., Jones, R.B., Schneider, J.R., Boone, D., Eves, E.M., Rosner, M.R., Gibbs, J.S., et al. (2009). Innate immune and chemically triggered oxidative stress modifies translational fidelity. Nature 462, 522–526.CrossRefGoogle Scholar
  36. Noma, A., Sakaguchi, Y., and Suzuki, T. (2009). Mechanistic characterization of the sulfur-relay system for eukaryotic 2-thiouridine biogenesis at tRNA wobble positions. Nucleic Acids Res 37, 1335–1352.CrossRefGoogle Scholar
  37. Pedrioli, P.G.A., Leidel, S., and Hofmann, K. (2008). Urm1 at the crossroad of modifications. ‘Protein Modifications: Beyond the Usual Suspects’ Review Series. EMBO Rep 9, 1196–1202.CrossRefGoogle Scholar
  38. Petroski, M.D., Salvesen, G.S., and Wolf, D.A. (2011). Urm1 couples sulfur transfer to ubiquitin-like protein function in oxidative stress. Proc Natl Acad Sci U S A 108, 1749–1750.CrossRefGoogle Scholar
  39. Pickart, C.M., and Fushman, D. (2004). Polyubiquitin chains: polymeric protein signals. Curr Opin Chem Biol 8, 610–616.CrossRefGoogle Scholar
  40. Rubio-Texeira, M. (2007). Urmylation controls Nil1p and Gln3p-dependent expression of nitrogen-catabolite repressed genes in Saccharomyces cerevisiae. FEBS Lett 581, 541–550.CrossRefGoogle Scholar
  41. Schlieker, C.D., Van der Veen, A.G., Damon, J.R., Spooner, E., and Ploegh, H.L. (2008). A functional proteomics approach links the ubiquitin-related modifier Urm1 to a tRNA modification pathway. Proc Natl Acad Sci U S A 105, 18255–18260.CrossRefGoogle Scholar
  42. Schmitz, J., Chowdhury, M.M., Hänzelmann, P., Nimtz, M., Lee, E.Y., Schindelin, H., and Leimkühler, S. (2008). The sulfurtransferase activity of Uba4 presents a link between ubiquitin-like protein conjugation and activation of sulfur carrier proteins. Biochemistry 47, 6479–6489.CrossRefGoogle Scholar
  43. Sen, G.C., and Ghosh, H.P. (1976). Role of modified nucleosides in tRNA: effect of modification of the 2-thiouridine derivative located at the 5′-end of the anticodon of yeast transfer RNA Lys2. Nucleic Acids Res 3, 523–535.CrossRefGoogle Scholar
  44. Shigi, N., Sakaguchi, Y., Suzuki, T., and Watanabe, K. (2006). Identification of two tRNA thiolation genes required for cell growth at extremely high temperatures. J Biol Chem 281, 14296–14306.CrossRefGoogle Scholar
  45. Singh, S., Tonelli, M., Tyler, R.C., Bahrami, A., Lee, M.S., and Markley, J.L. (2005). Three-dimensional structure of the AAH26994.1 protein from Mus musculus, a putative eukaryotic Urm1. Protein Sci 14, 2095–2102.CrossRefGoogle Scholar
  46. Sun, L.J., and Chen, Z.J. (2004). The novel functions of ubiquitination in signaling. Curr Opin Cell Biol 16, 119–126.CrossRefGoogle Scholar
  47. Svejstrup, J.Q. (2007). Elongator complex: how many roles does it play? Curr Opin Cell Biol 19, 331–336.CrossRefGoogle Scholar
  48. Ulrich, H.D. (2002). Degradation or maintenance: actions of the ubiquitin system on eukaryotic chromatin. Eukaryot Cell 1, 1–10.CrossRefGoogle Scholar
  49. Van der Veen, A.G., Schorpp, K., Schlieker, C., Buti, L., Damon, J.R., Spooner, E., Ploegh, H.L., and Jentsch, S. (2011). Role of the ubiquitin-like protein Urm1 as a noncanonical lysine-directed protein modifier. Proc Natl Acad Sci U S A 108, 1763–1770.CrossRefGoogle Scholar
  50. Wang, C.Y., Xi, J., Begley, T.P., and Nicholson, L.K. (2001). Solution structure of ThiS and implications for the evolutionary roots of ubiquitin. Nat Struct Biol 8, 47–51.CrossRefGoogle Scholar
  51. Wang, X.J., Yan, Q.F., and Guan, M.X. (2007). Deletion of the MTO2 gene related to tRNA modification causes a failure in mitochondrial RNA metabolism in the yeast Saccharomyces cerevisiae. FEBS Lett 581, 4228–4234.CrossRefGoogle Scholar
  52. Xi, J., Ge, Y., Kinsland, C., McLafferty, F.W., and Begley, T.P. (2001). Biosynthesis of the thiazole moiety of thiamin in Escherichia coli: identification of an acyldisulfide-linked protein-protein conjugate that is functionally analogous to the ubiquitin/E1 complex. Proc Natl Acad Sci U S A 98, 8513–8518.CrossRefGoogle Scholar
  53. Xu, J.J., Zhang, J.H., Wang, L., Zhou, J., Huang, H.D., Wu, J.H., Zhong, Y., and Shi, Y.Y. (2006). Solution structure of Urm1 and its implications for the origin of protein modifiers. Proc Natl Acad Sci U S A 103, 11625–11630.CrossRefGoogle Scholar
  54. Yu, J., and Zhou, C.Z. (2008). Crystal structure of the dimeric Urm1 from the yeast Saccharomyces cerevisiae. Proteins 71, 1050–1055.CrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Fengbin Wang
    • 1
  • Meiruo Liu
    • 1
  • Rui Qiu
    • 1
  • Chaoneng Ji
    • 1
  1. 1.Institute of GeneticsFudan UniversityShanghaiChina

Personalised recommendations