1. Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstrasse 4, Garching D-85747, Germany
2. Zurich–Basel Plant Science Center, Institute of Plant Biology, University of Zurich, Zollikerstrasse 107, 8008 Zurich, Switzerland
3. Cancer Research Center of Hawaii, University of Hawaii at Manoa, 1236 Lauhala Street, Honolulu, Hawaii 96813, USA
4. Cell and Molecular Biology Graduate Program, John A. Burns School of Medicine, University of Hawaii at Manoa, 651 Ilalo Street, Honolulu, Hawaii 96813, USA
5. Max-Planck-Institut für Biochemie, D-82152 Martinsried, Germany
6. School of Biosciences, Cardiff University, Cardiff CF10 3US, UK
7. Zentrum für medizinische Biotechnologie, Universität Duisburg-Essen, D-45117 Essen, Germany
8. Department of Plant and Microbial Biology, University of California, 111 Koshland Hall, Berkeley, California 94720-3102, USA
9. Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany
10. These authors contributed equally to this work.

Correspondence to: André S. Bachmann^3,4Markus Kaiser⁹Robert Dudler² Correspondence and requests for materials should be addressed to R.D. (Email: rdudler@botinst.uzh.ch), A.S.B. (Email: abachmann@crch.hawaii.edu) or M.K. (Email: markus.kaiser@cgc.mpg.de).

Abstract

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 planta¹. 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 Burkholderiales², 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 drugs³. Homologues of SylA and GlbA synthetase genes are found in some other pathogenic bacteria, including the human pathogen Burkholderia pseudomallei, the causative agent of melioidosis⁴. It is thus possible that these bacteria are capable of producing proteasome inhibitors of the syrbactin class.

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