A plant pathogen virulence factor inhibits the eukaryotic proteasome by a novel mechanism. Nature

Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstrasse 4, Garching D-85747, Germany.
Nature (Impact Factor: 41.46). 05/2008; 452(7188):755-8. DOI: 10.1038/nature06782
Source: PubMed


Pathogenic bacteria often use effector molecules to increase virulence. In most cases, the mode of action of effectors remains unknown. Strains of Pseudomonas syringae pv. syringae (Pss) secrete syringolin A (SylA), a product of a mixed non-ribosomal peptide/polyketide synthetase, in planta. Here we identify SylA as a virulence factor because a SylA-negative mutant in Pss strain B728a obtained by gene disruption was markedly less virulent on its host, Phaseolus vulgaris (bean). We show that SylA irreversibly inhibits all three catalytic activities of eukaryotic proteasomes, thus adding proteasome inhibition to the repertoire of modes of action of virulence factors. The crystal structure of the yeast proteasome in complex with SylA revealed a novel mechanism of covalent binding to the catalytic subunits. Thus, SylA defines a new class of proteasome inhibitors that includes glidobactin A (GlbA), a structurally related compound from an unknown species of the order Burkholderiales, for which we demonstrate a similar proteasome inhibition mechanism. As proteasome inhibitors are a promising class of anti-tumour agents, the discovery of a novel family of inhibitory natural products, which we refer to as syrbactins, may also have implications for the development of anti-cancer drugs. Homologues of SylA and GlbA synthetase genes are found in some other pathogenic bacteria, including the human pathogen Burkholderia pseudomallei, the causative agent of melioidosis. It is thus possible that these bacteria are capable of producing proteasome inhibitors of the syrbactin class.

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Available from: Michael Groll, Dec 30, 2013
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    • "Strains of P. syringae pv. syringae secrete syringolin A, a product of a mixed non-ribosomal peptide/polyketide synthetase , that has been identified as a virulence factor (Groll et al., 2008). Some of these effectors are able to elicit resistance 1095 and are thus called avirulence proteins (Avr). "
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    • "Inhibitory reaction mechanisms are shown for (A) the epoxyketone warhead in epoxomicin (Huber et al., 2012, Wei et al., 2012) and 1, (B) the natural a,b-unsaturated-amide system present in 2 (Groll et al., 2008), and (C and D) the enone warhead in the synthetic derivatives 4 and 5. "
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    • "syringae. This toxin specifically inhibits the proteasome in order to suppress host defenses (Groll et al., 2008; Schellenberg et al., 2010). Analyses of phytohormone levels after treatment of E-2- hexenal and DC3000 infection showed that there were no statistically significant differences in SA and JA levels between control and treatment (Figure A2 in Appendix). "
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