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.

Download full-text


Available from: Michael Groll, Dec 30, 2013
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Yield stability of legume crops is constrained by a number of pest and diseases. Major diseases are rusts, powdery and downy mildews, ascochyta blights, botrytis gray molds, anthracnoses, damping-off, root rots, collar rots, vascular wilts and white molds. Parasitic weeds, viruses, bacteria, nematodes and damages caused by chewing and sap-sucking insects add to this long list of constraints for legume production. Their incidence and relative importance together with current understanding of their interactions with the host plants are presented. State of the art of current achievements and limitations for breeding for biotic stress resistance are listed and critically discussed. The recent development of large scale phenotyping, genome sequencing and analysis of gene, protein and metabolite expressions can be of great help to further decipher plant-pathogen interactions and identify key resistance components that may be introgressed into crop plants through breeding.
    Full-text · Article · Jun 2015 · Critical Reviews in Plant Sciences
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hydroamination reactions involving the addition of an amine to an inactivated alkene are entropically prohibited and require strong chemical catalysts. While this synthetic process is efficient at generating substituted amines, there is no equivalent in small molecule-mediated enzyme inhibition. We report an unusual mechanism of proteasome inhibition that involves a hydroamination reaction of alkene derivatives of the epoxyketone natural product carmaphycin. We show that the carmaphycin enone first forms a hemiketal intermediate with the catalytic Thr1 residue of the proteasome before cyclization by an unanticipated intramolecular alkene hydroamination reaction, resulting in a stable six-membered morpholine ring. The carmaphycin enone electrophile, which does not undergo a 1,4-Michael addition as previously observed with vinyl sulfone and α,β-unsaturated amide-based inhibitors, is partially reversible and gives insight into the design of proteasome inhibitors for cancer chemotherapy.
    Full-text · Article · Jun 2014 · Chemistry & biology
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Green leaf volatiles (GLVs) are C6-molecules - alcohols, aldehydes, and esters - produced by plants upon herbivory or during pathogen infection. Exposure to this blend of volatiles induces defense-related responses in neighboring undamaged plants, thus assigning a role to GLVs in regulating plant defenses. Here we compared Arabidopsis thaliana ecotype Landsberg erecta (Ler) with a hydroperoxide lyase line, hpl1, unable to synthesize GLVs, for susceptibility to Pseudomonas syringae pv. tomato (DC3000). We found that the growth of DC3000 was significantly reduced in the hpl1 mutant. This phenomenon correlated with lower jasmonic acid (JA) levels and higher salicylic acid levels in the hpl1 mutant. Furthermore, upon infection, the JA-responsive genes VSP2 and LEC were only slightly or not induced, respectively, in hpl1. This suggests that the reduced growth of DC3000 in hpl1 plants is due to the constraint of JA-dependent responses. Treatment of hpl1 plants with E-2-hexenal, one of the more reactive GLVs, prior to infection with DC3000, resulted in increased growth of DC3000 in hpl1, thus complementing this mutant. Interestingly, the growth of DC3000 also increased in Ler plants treated with E-2-hexenal. This stronger growth was not dependent on the JA-signaling component MYC2, but on ORA59, an integrator of JA and ethylene signaling pathways, and on the production of coronatine by DC3000. GLVs may have multiple effects on plant-pathogen interactions, in this case reducing resistance to Pseudomonas syringae via JA and ORA59.
    Full-text · Article · Apr 2013 · Frontiers in Plant Science
Show more