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Prokaryotic ubiquitin-like protein (Pup), proteasomes and pathogenesis

Nature Reviews Microbiology volume 7, pages 485–491 (2009)Cite this article

Abstract

Proteasomes are ATP-dependent, multisubunit proteases that are found in all eukaryotes and archaea and some bacteria. In eukaryotes, the small protein ubiquitin is covalently attached in a post-translational manner to proteins that are targeted for proteasomal degradation. Despite the presence of proteasomes in many prokaryotes, ubiquitin or other post-translational protein modifiers were presumed to be absent from these organisms. Recently a prokaryotic ubiquitin-like protein, Pup, was found to target proteins for proteolysis by the Mycobacterium tuberculosis proteasome. The discovery of this ubiquitin-like modifier opens up the possibility that other bacteria may also have small post-translational protein tagging systems, with the ability to affect cellular processes.

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Figure 1: Overview of the eukaryotic ubiquitin–proteasome system.
Figure 2: Proposed model of the Pup–proteasome pathway in Mycobacterium tuberculosis.
Figure 3: Comparison of the pup regions of bacteria with and without proteasomes.

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References

  1. Pickart, C. M. & Cohen, R. E. Proteasomes and their kin: proteases in the machine age. Nature Rev. Mol. Cell Biol. 5, 177–187 (2004).

    Article  CAS  Google Scholar 

  2. Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Ventii, K. H. & Wilkinson, K. D. Protein partners of deubiquitinating enzymes. Biochem. J. 414, 161–175 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Wilkinson, K. D. Regulation of ubiquitin-dependent processes by deubiquitinating enzymes. FASEB J. 11, 1245–1256 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Marfany, G. & Denuc, A. To ubiquitinate or to deubiquitinate: it all depends on the partners. Biochem. Soc. Trans. 36, 833–838 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Kerscher, O., Felberbaum, R. & Hochstrasser, M. Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu. Rev. Cell Dev. Biol. 22, 159–180 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Johnson, E. S. Protein modification by SUMO. Annu. Rev. Biochem. 73, 355–382 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Chau, V. et al. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science 243, 1576–1583 (1989).

    Article  CAS  PubMed  Google Scholar 

  9. Hough, R. & Rechsteiner, M. Ubiquitin–lysozyme conjugates. Purification and susceptibility to proteolysis. J. Biol. Chem. 261, 2391–2399 (1986).

    CAS  PubMed  Google Scholar 

  10. Chen, Z. J. Ubiquitin signalling in the NF-κB pathway. Nature Cell Biol. 7, 758–765 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Haglund, K. & Dikic, I. Ubiquitylation and cell signaling. EMBO J. 24, 3353–3359 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. De Mot, R., Nagy, I., Walz, J. & Baumeister, W. Proteasomes and other self-compartmentalizing proteases in prokaryotes. Trends Microbiol. 7, 88–92 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Pearce, M. J., Mintseris, J., Ferreyra, J., Gygi, S. P. & Darwin, K. H. Ubiquitin-like protein involved in the proteasome pathway of Mycobacterium tuberculosis. Science 322, 1104–1107 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Butler, S. M., Festa, R. F., Pearce, M. J. & Darwin, K. H. Self-compartmentalized bacterial proteases and pathogenesis. Mol. Microbiol. 60, 553–562 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Zwickl, P., Baumeister, W. & Goldberg, A. L. in Proteasomes: The World of Regulatory Proteolysis (eds Hilt, W. & Wolf, D. H.) 8–18 (Eurekah.com, Georgetown, Texas, 2000).

    Google Scholar 

  16. Lin, G. et al. Mycobacterium tuberculosis prcBA genes encode a gated proteasome. Mol. Microbiol. 59, 1405–1416 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Hu, G. et al. Structure of the Mycobacterium tuberculosis proteasome and mechanism of inhibition by a peptidyl boronate. Mol. Microbiol. 59, 1417–1428 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Löwe, J. et al. Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 Å resolution. Science 268, 533–539 (1995).

    Article  PubMed  Google Scholar 

  19. Nagy, I., Tamura, T., Vanderleyden, J., Baumeister, W. & De Mot, R. The 20S proteasome of Streptomyces coelicolor. J. Bacteriol. 180, 5448–5453 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kwon, Y. D., Nagy, I., Adams, P. D., Baumeister, W. & Jap, B. K. Crystal structures of the Rhodococcus proteasome with and without its pro-peptides: implications for the role of the pro-peptide in proteasome assembly. J. Mol. Biol. 335, 233–245 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Tamura, T. et al. The first characterization of a eubacterial proteasome: the 20S complex of Rhodococcus. Curr. Biol. 5, 766–774 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Darwin, K. H., Ehrt, S., Weich, N., Gutierrez-Ramos, J.-C. & Nathan, C. F. The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide. Science 302, 1963–1966 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Pouch, M.-N., Cournoyer, B. & Baumeister, W. Characterization of the 20S proteasome from the actinomycete Frankia. Mol. Microbiol. 35, 368–377 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Knipfer, N. & Shrader, T. E. Inactivation of the 20S proteasome in Mycobacterium smegmatis. Mol. Microbiol. 25, 375–383 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Smith, D. M. et al. ATP binding to PAN or the 26S ATPases causes association with the 20S proteasome, gate opening, and translocation of unfolded proteins. Mol. Cell 20, 687–698 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. MacMicking, J. D. et al. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc. Natl Acad. Sci. USA 94, 5243–5248 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shiloh, M. U. & Nathan, C. F. Reactive nitrogen intermediates and the pathogenesis of Salmonella and mycobacteria. Curr. Opin. Microbiol. 3, 35–42 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Nagy, I., Geert, S., Vanderleyden, J. & De Mot, R. Further sequence analysis of the DNA regions with the Rhodococcus 20S proteasome structural genes reveals extensive homology with Mycobacterium leprae. DNA Seq. 7, 225–228 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Festa, R. A., Pearce, M. J. & Darwin, K. H. Characterization of the proteasome accessory factor (paf) operon in Mycobacterium tuberculosis. J. Bacteriol. 189, 3044–3050 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gandotra, S., Schnappinger, D., Monteleone, M., Hillen, W. & Ehrt, S. In vivo gene silencing identifies the Mycobacterium tuberculosis proteasome as essential for the bacteria to persist in mice. Nature Med. 13, 1515–1520 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Pearce, M. J. et al. Identification of substrates of the Mycobacterium tuberculosis proteasome. EMBO J. 25, 5423–5432 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Singh, A., Mai, D., Kumar, A. & Steyn, A. J. Dissecting virulence pathways of Mycobacterium tuberculosis through protein–protein association. Proc. Natl Acad. Sci USA 103, 11346–11351 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Burns, K. E., Liu, W. T., Boshoff, H. I., Dorrestein, P. C. & Barry, C. E. 3rd. Proteasomal protein degradation in mycobacteria is dependent upon a prokaryotic ubiquitin-like protein. J. Biol. Chem. 284, 3069–3075 (2008).

    Article  PubMed  Google Scholar 

  34. Soding, J., Biegert, A. & Lupas, A. N. The HHpred interactive server for protein homology detection and structure prediction. Nucleic Acids Res. 33, W244–W248 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Lehmann, C. et al. YbdK is a carboxylate-amine ligase with a g-glutamyl:cysteine ligase activity: crystal structure and enzymatic assays. Proteins 56, 376–383 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Iyer, L. M., Burroughs, A. M. & Aravind, L. Unraveling the biochemistry and provenance of pupylation: a prokaryotic analog of ubiquitination. Biol. Direct 3, 45 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Altschul, S. F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang, X. et al. The N-terminal coiled coil of the Rhodococcus erythropolis ARC AAA ATPase is neither necessary for oligomerization nor nucleotide hydrolysis. J. Struct. Biol. 146, 155–165 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Darwin, K. H., Lin, G., Chen, Z., Li, H. & Nathan, C. Characterization of a Mycobacterium tuberculosis proteasomal ATPase homologue. Mol. Microbiol. 55, 561–571 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Kessler, D. Enzymatic activation of sulfur for incorporation into biomolecules in prokaryotes. FEMS Microbiol. Rev. 30, 825–840 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Pedrioli, P. G., Leidel, S. & Hofmann, K. Urm1 at the crossroad of modifications. 'Protein Modifications: Beyond the Usual Suspects' Review Series. EMBO Rep. 9, 1196–1202 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Leidel, S. et al. Ubiquitin-related modifier Urm1 acts as a sulphur carrier in thiolation of eukaryotic transfer RNA. Nature 458, 228–232 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. 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. USA 105, 18255–18260 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ikeuchi, Y., Shigi, N., Kato, J., Nishimura, A. & Suzuki, T. Mechanistic insights into sulfur relay by multiple sulfur mediators involved in thiouridine biosynthesis at tRNA wobble positions. Mol. Cell 21, 97–108 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Numata, T., Ikeuchi, Y., Fukai, S., Suzuki, T. & Nureki, O. Snapshots of tRNA sulphuration via an adenylated intermediate. Nature 442, 419–424 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Cerdeno-Tarraga, A. M. et al. Extensive DNA inversions in the B. fragilis genome control variable gene expression. Science 307, 1463–1465 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Giannakis, M., Chen, S. L., Karam, S. M., Engstrand, L. & Gordon, J. I. Helicobacter pylori evolution during progression from chronic atrophic gastritis to gastric cancer and its impact on gastric stem cells. Proc. Natl Acad. Sci. USA 105, 4358–4363 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rytkonen, A. & Holden, D. W. Bacterial interference of ubiquitination and deubiquitination. Cell Host Microbe 1, 13–22 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ozkaynak, E., Finley, D., Solomon, M. J. & Varshavsky, A. The yeast ubiquitin genes: a family of natural gene fusions. EMBO J. 6, 1429–1439 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jin, J., Li, X., Gygi, S. P. & Harper, J. W. Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging. Nature 447, 1135–1138 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Chiu, Y. H., Sun, Q. & Chen, Z. J. E1–L2 activates both ubiquitin and FAT10. Mol. Cell 27, 1014–1023 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Striebel, F. et al. Bacterial ubiquitin-like modifier Pup is deamidated and conjugated to substrates by distinct but homologous enzymes. Nature Struct. Mol. Biol. 17 May 2009 (doi:10.1038/nsmb.1597).

    Article  CAS  Google Scholar 

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Acknowledgements

I am grateful to A. Darwin, I. Mohr and H. Ovaa for critical review of this manuscript. I thank the anonymous referees for excellent suggestions and important corrections. I am supported by National Institutes of Health (NIH) grants AI065437 and HL092774 and a Center For AIDS Research Pilot Project grant (NIH S P30 A1027742-17).

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  1. K. Heran Darwin is at the Department of Microbiology, New York University School of Medicine, 550 First Avenue MSB 236, New York, New York 10016, USA. heran.darwin@med.nyu.edu,

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DATABASES

Entrez Genome Project

Bacteroides fragilis

Corynebacterium glutamicum

Escherichia coli

Helicobacter pylori

Methanococcus jannaschii

Mycobacterium smegmatis

Mycobacterium tuberculosis

Thermoplasma acidophilum

FURTHER INFORMATION

Microbial Genome Database

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Darwin, K. Prokaryotic ubiquitin-like protein (Pup), proteasomes and pathogenesis. Nat Rev Microbiol 7, 485–491 (2009). https://doi.org/10.1038/nrmicro2148

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