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The Pup-Proteasome System of Mycobacteria

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  • Authors: Nadine J. Bode1, K. Heran Darwin2
  • Editors: Graham F. Hatfull3, William R. Jacobs Jr.4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: New York University School of Medicine, Department of Microbiology, 550 First Avenue, MSB 236, New York, NY 10016; 2: New York University School of Medicine, Department of Microbiology, 550 First Avenue, MSB 236, New York, NY 10016; 3: University of Pittsburgh, Pittsburgh, PA; 4: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY
    • Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0008-2013
  • Received 08 April 2013 Accepted 26 July 2013 Published 12 September 2014
  • K. H. Darwin, [email protected]
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  • Abstract:

    Proteasomes are ATP-dependent, barrel-shaped proteases found in all three domains of life. In eukaryotes, proteins are typically targeted for degradation by posttranslational modification with the small protein ubiquitin. In 2008, the first bacterial protein modifier, Pup (rokaryotic biquitin-like rotein), was identified in . Functionally analogous to ubiquitin, conjugation with Pup serves as a signal for degradation by the mycobacterial proteasome. Proteolysis-dependent and -independent functions of the proteasome are essential for virulence of this successful pathogen. In this article we describe the discovery of the proteasome as a key player in tuberculosis pathogenesis and the biology and biochemistry of the Pup-proteasome system.

  • Citation: Bode N, Darwin K. 2014. The Pup-Proteasome System of Mycobacteria. Microbiol Spectrum 2(5):MGM2-0008-2013. doi:10.1128/microbiolspec.MGM2-0008-2013.

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2014-09-12
2021-04-17

Abstract:

Proteasomes are ATP-dependent, barrel-shaped proteases found in all three domains of life. In eukaryotes, proteins are typically targeted for degradation by posttranslational modification with the small protein ubiquitin. In 2008, the first bacterial protein modifier, Pup (rokaryotic biquitin-like rotein), was identified in . Functionally analogous to ubiquitin, conjugation with Pup serves as a signal for degradation by the mycobacterial proteasome. Proteolysis-dependent and -independent functions of the proteasome are essential for virulence of this successful pathogen. In this article we describe the discovery of the proteasome as a key player in tuberculosis pathogenesis and the biology and biochemistry of the Pup-proteasome system.

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The Pup-Proteasome System of Mycobacteria
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Citation: Bode N, Darwin K. 2014. The pup-proteasome system of mycobacteria. microbiolspec 2(5): doi:10.1128/microbiolspec.MGM2-0008-2013
/content/microbiolspec/10.1128/microbiolspec.MGM2-0008-2013.fig1
FIGURE 1
Eukaryotic ubiquitin-proteasome system. Ubiquitin (Ub) precursors are processed to expose a C-terminal di-glycine motif. The conjugation-competent Ub is adenylated and subsequently bound in a high-energy thioester bond by the E1-activating enzyme. Ub is then transferred to the catalytic cysteine of an E2-conjugating enzyme. Ub can be ligated to substrates with the help of E3-ligases. Typically, tetra-Ub chains linked at lysine 48 are recognized by the 26S proteasome. Deubiquitylases can remove Ub from substrates.
microbiolspec/2/5/MGM2-0008-2013-fig1_thmb.gif
microbiolspec/2/5/MGM2-0008-2013-fig1.gif
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FIGURE 1

Eukaryotic ubiquitin-proteasome system. Ubiquitin (Ub) precursors are processed to expose a C-terminal di-glycine motif. The conjugation-competent Ub is adenylated and subsequently bound in a high-energy thioester bond by the E1-activating enzyme. Ub is then transferred to the catalytic cysteine of an E2-conjugating enzyme. Ub can be ligated to substrates with the help of E3-ligases. Typically, tetra-Ub chains linked at lysine 48 are recognized by the 26S proteasome. Deubiquitylases can remove Ub from substrates.

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0008-2013
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FIGURE 2
Mycobacterial pupylation pathway. Pup is deamidated at the C-terminal glutamine by Dop (deamidase of Pup). The Pup ligase PafA phosphorylates the C-terminal γ-carboxylate of Pup and then conjugates Pup to lysine residues of target proteins via an isopeptide bond. The mycobacterial proteasome and its cognate ATPase Mpa degrade pupylated proteins. Dop also acts as a depupylase, allowing for Pup to be recycled.
microbiolspec/2/5/MGM2-0008-2013-fig2_thmb.gif
microbiolspec/2/5/MGM2-0008-2013-fig2.gif
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FIGURE 2

Mycobacterial pupylation pathway. Pup is deamidated at the C-terminal glutamine by Dop (deamidase of Pup). The Pup ligase PafA phosphorylates the C-terminal γ-carboxylate of Pup and then conjugates Pup to lysine residues of target proteins via an isopeptide bond. The mycobacterial proteasome and its cognate ATPase Mpa degrade pupylated proteins. Dop also acts as a depupylase, allowing for Pup to be recycled.

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0008-2013
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FIGURE 3
Genomic organization of PPS genes in mycobacteria. Gene data are from http://tuberculist.epfl.ch/. * and are cotranscribed with in H37Rv ( 46 ). However, no apparent contribution to pupylation has been demonstrated for PafB or PafC ( 40 ).
microbiolspec/2/5/MGM2-0008-2013-fig3_thmb.gif
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FIGURE 3

Genomic organization of PPS genes in mycobacteria. Gene data are from http://tuberculist.epfl.ch/. * and are cotranscribed with in H37Rv ( 46 ). However, no apparent contribution to pupylation has been demonstrated for PafB or PafC ( 40 ).

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0008-2013
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The Pup-Proteasome System of Mycobacteria
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Citation: Bode N, Darwin K. 2014. The pup-proteasome system of mycobacteria. microbiolspec 2(5): doi:10.1128/microbiolspec.MGM2-0008-2013
/content/microbiolspec/10.1128/microbiolspec.MGM2-0008-2013.T1
TABLE 1
Summary of phenotypes observed for mutants of the PPS
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TABLE 1

Summary of phenotypes observed for mutants of the PPS

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0008-2013

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