Chapter 32 : The Pup-Proteasome System of Mycobacteria

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Murine models of tuberculosis have implicated the production of nitric oxide (NO) by activated macrophages as a pivotal part of the immune response, because mice lacking inducible nitric oxide synthase (iNOS) readily succumb to infection with ( ). Formation of reactive nitrogen and oxygen intermediates (RNIs and ROIs) is toxic to a variety of microbes (reviewed in reference ). The free radical NO is neutral and hydrophobic, allowing it to pass cellular and bacterial membranes. Reaction with superoxide generated by NADPH phagocyte oxidase results in the formation of the particularly destructive product peroxynitrite. The cytotoxic effects of RNI and ROI include DNA strand breakage, lipid peroxidation, and protein damage (reviewed in references , and ). Although the importance of NO has not yet been irrevocably demonstrated in humans, several studies suggest a role of host-derived RNI in control of tuberculosis (reviewed in references and ).

Citation: Bode N, Darwin K. 2014. The Pup-Proteasome System of Mycobacteria, p 667-680. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0008-2013
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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.

Citation: Bode N, Darwin K. 2014. The Pup-Proteasome System of Mycobacteria, p 667-680. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. 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.

Citation: Bode N, Darwin K. 2014. The Pup-Proteasome System of Mycobacteria, p 667-680. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. 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 ( ). However, no apparent contribution to pupylation has been demonstrated for PafB or PafC ( ).

Citation: Bode N, Darwin K. 2014. The Pup-Proteasome System of Mycobacteria, p 667-680. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0008-2013
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Table 1

Summary of phenotypes observed for mutants of the PPS

Citation: Bode N, Darwin K. 2014. The Pup-Proteasome System of Mycobacteria, p 667-680. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0008-2013

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