Skip to main content
NCBI home page
Protein & Cell logoLink to Protein & Cell
. 2011 Sep 9;2(8):612–619. doi: 10.1007/s13238-011-1074-6

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

Fengbin Wang 1, Meiruo Liu 1, Rui Qiu 1, Chaoneng Ji 1,✉
PMCID: PMC4875326  PMID: 21904977

Abstract

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.

Keywords: Urm1 system, tRNA modification, Ub-like protein modification

References

  1. Abbink T.E.M., Berkhout B. HIV-1 reverse transcription initiation: a potential target for novel antivirals? Virus Res. 2008;134:4–18. doi: 10.1016/j.virusres.2007.12.009. [DOI] [PubMed] [Google Scholar]
  2. Agris P.F. Bringing order to translation: the contributions of transfer RNA anticodon-domain modifications. EMBO Rep. 2008;9:629–635. doi: 10.1038/embor.2008.104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Behrens P., Brinkmann U., Wellmann A. CSE1L/CAS: its role in proliferation and apoptosis. Apoptosis. 2003;8:39–44. doi: 10.1023/A:1021644918117. [DOI] [PubMed] [Google Scholar]
  4. Björk G.R., Huang B., Persson O.P., Byström A.S. A conserved modified wobble nucleoside (mcm5s2U) in lysyl-tRNA is required for viability in yeast. RNA. 2007;13:1245–1255. doi: 10.1261/rna.558707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bordo D., Bork P. The rhodanese/Cdc25 phosphatase superfamily. Sequence-structure-function relations. EMBO Rep. 2002;3:741–746. doi: 10.1093/embo-reports/kvf150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ciechanover A., Heller H., Katzetzion R., Hershko A. Activation of the Heat-Stable Polypeptide of the Atp-Dependent Proteolytic System. Proc Natl Acad Sci U S A. 1981;78:761–765. doi: 10.1073/pnas.78.2.761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dewez M., Bauer F., Dieu M., Raes M., Vandenhaute J., Hermand D. The conserved Wobble uridine tRNA thiolase Ctu1-Ctu2 is required to maintain genome integrity. Proc Natl Acad Sci U S A. 2008;105:5459–5464. doi: 10.1073/pnas.0709404105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fichtner L., Jablonowski D., Schierhorn A., Kitamoto H.K., Stark M.J.R., Schaffrath R. Elongator’s toxin-target (TOT) function is nuclear localization sequence dependent and suppressed by post-translational modification. Mol Microbiol. 2003;49:1297–1307. doi: 10.1046/j.1365-2958.2003.03632.x. [DOI] [PubMed] [Google Scholar]
  9. Furukawa K., Mizushima N., Noda T., Ohsumi Y. A protein conjugation system in yeast with homology to biosynthetic enzyme reaction of prokaryotes. J Biol Chem. 2000;275:7462–7465. doi: 10.1074/jbc.275.11.7462. [DOI] [PubMed] [Google Scholar]
  10. Goehring A.S., Rivers D.M., Sprague G.F., Jr. Attachment of the ubiquitin-related protein Urm1p to the antioxidant protein Ahp1p. Eukaryot Cell. 2003;2:930–936. doi: 10.1128/EC.2.5.930-936.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Goehring A.S., Rivers D.M., Sprague G.F., Jr. Urmylation: a ubiquitin-like pathway that functions during invasive growth and budding in yeast. Mol Biol Cell. 2003;14:4329–4341. doi: 10.1091/mbc.E03-02-0079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Haas A.L., Warms J.V.B., Hershko A., Rose I.A. Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation. J Biol Chem. 1982;257:2543–2548. [PubMed] [Google Scholar]
  13. Hershko A., Ciechanover A., Varshavsky A. The ubiquitin system. Nat Med. 2000;6:1073–1081. doi: 10.1038/80384. [DOI] [PubMed] [Google Scholar]
  14. Hochstrasser M. Evolution and function of ubiquitin-like protein-conjugation systems. Nat Cell Biol. 2000;2:E153–E157. doi: 10.1038/35019643. [DOI] [PubMed] [Google Scholar]
  15. Hochstrasser M. Origin and function of ubiquitin-like proteins. Nature. 2009;458:422–429. doi: 10.1038/nature07958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Huang B., Lu J., Byström A.S. A genome-wide screen identifies genes required for formation of the wobble nucleoside 5-methoxycarbonylmethyl-2-thiouridine in Saccharomyces cerevisiae. RNA. 2008;14:2183–2194. doi: 10.1261/rna.1184108. [DOI] [PMC free article] [PubMed] [Google 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., Maupin-Furlow J.A. Ubiquitin-like small archaeal modifier proteins (SAMPs) in Haloferax volcanii. Nature. 2010;463:54–60. doi: 10.1038/nature08659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Isel C., Lanchy J.M., Le Grice S.F.J., Ehresmann C., Ehresmann B., Marquet R. Specific initiation and switch to elongation of human immunodeficiency virus type 1 reverse transcription require the post-transcriptional modifications of primer tRNA3Lys. EMBO J. 1996;15:917–924. [PMC free article] [PubMed] [Google Scholar]
  19. Isel C., Marquet R., Keith G., Ehresmann C., Ehresmann B. Modified nucleotides of tRNA(3Lys) modulate primer/template loop-loop interaction in the initiation complex of HIV-1 reverse transcription. J Biol Chem. 1993;268:25269–25272. [PubMed] [Google Scholar]
  20. Iyer L.M., Burroughs A.M., Aravind L. The prokaryotic antecedents of the ubiquitin-signaling system and the early evolution of ubiquitin-like beta-grasp domains. Genome Biol. 2006;7:R60. doi: 10.1186/gb-2006-7-7-r60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jeong J.S., Kwon S.J., Kang S.W., Rhee S.G., Kim K. Purification and characterization of a second type thioredoxin peroxidase (type II TPx) from Saccharomyces cerevisiae. Biochemistry. 1999;38:776–783. doi: 10.1021/bi9817818. [DOI] [PubMed] [Google Scholar]
  22. Johansson M.J.O., Esberg A., Huang B., Björk G.R., Byström A.S. Eukaryotic wobble uridine modifications promote a functionally redundant decoding system. Mol Cell Biol. 2008;28:3301–3312. doi: 10.1128/MCB.01542-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lake M.W., Wuebbens M.M., Rajagopalan K.V., Schindelin H. Mechanism of ubiquitin activation revealed by the structure of a bacterial MoeB-MoaD complex. Nature. 2001;414:325–329. doi: 10.1038/35104586. [DOI] [PubMed] [Google Scholar]
  24. Lee J., Spector D., Godon C., Labarre J., Toledano M.B. A new antioxidant with alkyl hydroperoxide defense properties in yeast. J Biol Chem. 1999;274:4537–4544. doi: 10.1074/jbc.274.8.4537. [DOI] [PubMed] [Google Scholar]
  25. Leidel S., Pedrioli P.G.A., Bucher T., Brost R., Costanzo M., Schmidt A., Aebersold R., Boone C., Hofmann K., Peter M. Ubiquitin-related modifier Urm1 acts as a sulphur carrier in thiolation of eukaryotic transfer RNA. Nature. 2009;458:228–232. doi: 10.1038/nature07643. [DOI] [PubMed] [Google Scholar]
  26. Ling J.Q., Söll D. Severe oxidative stress induces protein mistranslation through impairment of an aminoacyl-tRNA synthetase editing site. Proc Natl Acad Sci U S A. 2010;107:4028–4033. doi: 10.1073/pnas.1000315107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lu J., Esberg A., Huang B., Byström A.S. Kluyveromyces lactis gamma-toxin, a ribonuclease that recognizes the anticodon stem loop of tRNA. Nucleic Acids Res. 2008;36:1072–1080. doi: 10.1093/nar/gkm1121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lu J., Huang B., Esberg A., Johansson M.J.O., Byström A.S. The Kluyveromyces lactis gamma-toxin targets tRNA anticodons. RNA. 2005;11:1648–1654. doi: 10.1261/rna.2172105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Marelja Z., Stöcklein W., Nimtz M., Leimkühler S. 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. 2008;283:25178–25185. doi: 10.1074/jbc.M804064200. [DOI] [PubMed] [Google Scholar]
  30. Miranda H.V., Nembhard N., Su D., Hepowit N., Krause D.J., Pritz J.R., Phillips C., Söll D., Maupin-Furlow J.A. E1- and ubiquitin-like proteins provide a direct link between protein conjugation and sulfur transfer in archaea. Proc Natl Acad Sci U S A. 2011;108:4417–4422. doi: 10.1073/pnas.1018151108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mueller E.G. Trafficking in persulfides: delivering sulfur in biosynthetic pathways. Nat Chem Biol. 2006;2:185–194. doi: 10.1038/nchembio779. [DOI] [PubMed] [Google Scholar]
  32. Nakai Y., Nakai M., Hayashi H. Thio-modification of yeast cytosolic tRNA requires a ubiquitin-related system that resembles bacterial sulfur transfer systems. J Biol Chem. 2008;283:27469–27476. doi: 10.1074/jbc.M804043200. [DOI] [PubMed] [Google Scholar]
  33. Nakai Y., Nakai M., Hayashi H., Kagamiyama H. Nuclear localization of yeast Nfs1p is required for cell survival. J Biol Chem. 2001;276:8314–8320. doi: 10.1074/jbc.M007878200. [DOI] [PubMed] [Google Scholar]
  34. Nakai Y., Umeda N., Suzuki T., Nakai M., Hayashi H., Watanabe K., Kagamiyama H. Yeast Nfs1p is involved in thiomodification of both mitochondrial and cytoplasmic tRNAs. J Biol Chem. 2004;279:12363–12368. doi: 10.1074/jbc.M312448200. [DOI] [PubMed] [Google 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. Innate immune and chemically triggered oxidative stress modifies translational fidelity. Nature. 2009;462:522–526. doi: 10.1038/nature08576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Noma A., Sakaguchi Y., Suzuki T. Mechanistic characterization of the sulfur-relay system for eukaryotic 2-thiouridine biogenesis at tRNA wobble positions. Nucleic Acids Res. 2009;37:1335–1352. doi: 10.1093/nar/gkn1023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Pedrioli P.G.A., Leidel S., Hofmann K. Urm1 at the crossroad of modifications. ‘Protein Modifications: Beyond the Usual Suspects’ Review Series. EMBO Rep. 2008;9:1196–1202. doi: 10.1038/embor.2008.209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Petroski M.D., Salvesen G.S., Wolf D.A. Urm1 couples sulfur transfer to ubiquitin-like protein function in oxidative stress. Proc Natl Acad Sci U S A. 2011;108:1749–1750. doi: 10.1073/pnas.1019043108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Pickart C.M., Fushman D. Polyubiquitin chains: polymeric protein signals. Curr Opin Chem Biol. 2004;8:610–616. doi: 10.1016/j.cbpa.2004.09.009. [DOI] [PubMed] [Google Scholar]
  40. Rubio-Texeira M. Urmylation controls Nil1p and Gln3p-dependent expression of nitrogen-catabolite repressed genes in Saccharomyces cerevisiae. FEBS Lett. 2007;581:541–550. doi: 10.1016/j.febslet.2007.01.019. [DOI] [PubMed] [Google Scholar]
  41. Schlieker C.D., Van der Veen A.G., Damon J.R., Spooner E., Ploegh H.L. A functional proteomics approach links the ubiquitin-related modifier Urm1 to a tRNA modification pathway. Proc Natl Acad Sci U S A. 2008;105:18255–18260. doi: 10.1073/pnas.0808756105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Schmitz J., Chowdhury M.M., Hänzelmann P., Nimtz M., Lee E.Y., Schindelin H., Leimkühler S. The sulfurtransferase activity of Uba4 presents a link between ubiquitin-like protein conjugation and activation of sulfur carrier proteins. Biochemistry. 2008;47:6479–6489. doi: 10.1021/bi800477u. [DOI] [PubMed] [Google Scholar]
  43. Sen G.C., Ghosh H.P. 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. 1976;3:523–535. doi: 10.1093/nar/3.3.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Shigi N., Sakaguchi Y., Suzuki T., Watanabe K. Identification of two tRNA thiolation genes required for cell growth at extremely high temperatures. J Biol Chem. 2006;281:14296–14306. doi: 10.1074/jbc.M511675200. [DOI] [PubMed] [Google Scholar]
  45. Singh S., Tonelli M., Tyler R.C., Bahrami A., Lee M.S., Markley J.L. Three-dimensional structure of the AAH26994.1 protein from Mus musculus, a putative eukaryotic Urm1. Protein Sci. 2005;14:2095–2102. doi: 10.1110/ps.051577605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Sun L.J., Chen Z.J. The novel functions of ubiquitination in signaling. Curr Opin Cell Biol. 2004;16:119–126. doi: 10.1016/j.ceb.2004.02.005. [DOI] [PubMed] [Google Scholar]
  47. Svejstrup J.Q. Elongator complex: how many roles does it play? Curr Opin Cell Biol. 2007;19:331–336. doi: 10.1016/j.ceb.2007.04.005. [DOI] [PubMed] [Google Scholar]
  48. Ulrich H.D. Degradation or maintenance: actions of the ubiquitin system on eukaryotic chromatin. Eukaryot Cell. 2002;1:1–10. doi: 10.1128/EC.1.1.1-10.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Van der Veen A.G., Schorpp K., Schlieker C., Buti L., Damon J.R., Spooner E., Ploegh H.L., Jentsch S. Role of the ubiquitin-like protein Urm1 as a noncanonical lysine-directed protein modifier. Proc Natl Acad Sci U S A. 2011;108:1763–1770. doi: 10.1073/pnas.1014402108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Wang C.Y., Xi J., Begley T.P., Nicholson L.K. Solution structure of ThiS and implications for the evolutionary roots of ubiquitin. Nat Struct Biol. 2001;8:47–51. doi: 10.1038/83041. [DOI] [PubMed] [Google Scholar]
  51. Wang X.J., Yan Q.F., Guan M.X. Deletion of the MTO2 gene related to tRNA modification causes a failure in mitochondrial RNA metabolism in the yeast Saccharomyces cerevisiae. FEBS Lett. 2007;581:4228–4234. doi: 10.1016/j.febslet.2007.07.067. [DOI] [PubMed] [Google Scholar]
  52. Xi J., Ge Y., Kinsland C., McLafferty F.W., Begley T.P. 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. 2001;98:8513–8518. doi: 10.1073/pnas.141226698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Xu J.J., Zhang J.H., Wang L., Zhou J., Huang H.D., Wu J.H., Zhong Y., Shi Y.Y. Solution structure of Urm1 and its implications for the origin of protein modifiers. Proc Natl Acad Sci U S A. 2006;103:11625–11630. doi: 10.1073/pnas.0604876103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Yu J., Zhou C.Z. Crystal structure of the dimeric Urm1 from the yeast Saccharomyces cerevisiae. Proteins. 2008;71:1050–1055. doi: 10.1002/prot.21975. [DOI] [PubMed] [Google Scholar]

Articles from Protein & Cell are provided here courtesy of Oxford University Press

RESOURCES