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Category: Microbial Genetics and Molecular Biology
The Pup-Proteasome System of Mycobacteria, Page 1 of 2
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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 M. tuberculosis ( 1 ). Formation of reactive nitrogen and oxygen intermediates (RNIs and ROIs) is toxic to a variety of microbes (reviewed in reference 2 ). 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 3 , 4 , and 5 ). Although the importance of NO has not yet been irrevocably demonstrated in humans, several in vitro studies suggest a role of host-derived RNI in control of tuberculosis (reviewed in references 2 and 6 ).
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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.
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.
Genomic organization of PPS genes in mycobacteria. Gene data are from http://tuberculist.epfl.ch/. *pafB and pafC are cotranscribed with pafA in M. tuberculosis H37Rv ( 46 ). However, no apparent contribution to pupylation has been demonstrated for PafB or PafC ( 40 ).
Summary of phenotypes observed for mutants of the PPS a