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A Common Toxin Fold Mediates Microbial Attack and Plant Defense

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A Common Toxin Fold Mediates Microbial Attack and Plant Defense A common toxin fold mediates microbial attack and plant defense Christian Ottmanna,b,1, Borries Luberackia,1,2, Isabell Ku¨ fnerc,1, Wolfgang Kocha, Fre´ de´ ric Brunnerc, Michael Weyandb, Laura Mattinend, Minna Pirhonend, Gregor Anderluhe, Hanns Ulrich Seitza,3, Thorsten Nu¨ rnbergerc,3, and Claudia Oeckinga,3 aCenter for Plant Molecular Biology–Plant Physiology, University of Tu¨bingen, D-72076 Tu¨bingen, Germany; bChemical Genomics Centre, D-44227 Dortmund, Germany; cCenter for Plant Molecular Biology–Plant Biochemistry, University of Tu¨bingen, D-72076 Tu¨bingen, Germany; dUniversity of Helsinki, Department of Applied Biology, FIN-00014, Helsinki, Finland; and eUniversity of Ljubljana, Department of Biology, SLO-1000 Ljubljana, Slovenia Edited by Jeffery L. Dangl, The University of North Carolina, Chapel Hill, NC, and approved May 5, 2009 (received for review March 4, 2009) Many plant pathogens secrete toxins that enhance microbial vir- recognition of microbial patterns and effectors, plants also ulence by killing host cells. Usually, these toxins are produced by possess capacities to sense host-derived ‘‘damage’’ patterns that particular microbial taxa, such as bacteria or fungi. In contrast, originate, for example, from the degradation of the plant cell wall many bacterial, fungal and oomycete species produce necrosis and by microbial hydrolytic enzyme activities (10). Paradoxically, ethylene-inducing peptide 1 (Nep1)-like proteins (NLPs) that trig- some phytopathogenic microbe-derived cytolytic toxins have ger leaf necrosis and immunity-associated responses in various also been reported to elicit plant defenses, including Fusarium plants. We have determined the crystal structure of an NLP from spp.-derived fumonisin B1, Phomopsis amygdali-derived fusi- the phytopathogenic oomycete Pythium aphanidermatum to 1.35Å coccin, or the host-selective toxin, victorin, from Cochliobolus resolution. The protein fold exhibits structural similarities to cyto- victoriae (6, 11). However, for virtually all microbial toxins with lytic toxins produced by marine organisms (actinoporins). Compu- plant defense-stimulating potential, it is unknown whether ac- tational modeling of the 3-dimensional structure of NLPs from tivation of plant defenses results from toxin-induced cellular another oomycete, Phytophthora parasitica, and from the phyto- distress or, independently of toxin action, from recognition of pathogenic bacterium, Pectobacterium carotovorum, revealed a toxins as microbial patterns by plant pattern-recognition high extent of fold conservation. Expression of the 2 oomycete receptors. NLPs in an nlp-deficient P. carotovorum strain restored bacterial NLPs constitute a superfamily of proteins that are produced virulence, suggesting that NLPs of prokaryotic and eukaryotic by various phytopathogenic micro-organisms, comprising both origins are orthologous proteins. NLP mutant protein analyses prokaryotic and eukaryotic organisms (3, 7, 12, 13). Necrosis and revealed that identical structural properties were required to cause ethylene-inducing peptide 1 (Nep1)-like proteins (NLPs) trigger plasma membrane permeabilization and cytolysis in plant cells, as well as to restore bacterial virulence. In sum, NLPs are conserved leaf necrosis that is genetically distinct from immunity- virulence factors whose taxonomic distribution is exceptional for associated programmed cell death (11) and stimulate immunity- microbial phytotoxins, and that contribute to host infection by associated defenses in all dicotyledonous plants tested, but not plasma membrane destruction and cytolysis. We further show that in monocotyledonous plants (3, 7). Hence, NLPs were proposed NLP-mediated phytotoxicity and plant defense gene expression to have dual functions in plant pathogen interactions, acting both share identical fold requirements, suggesting that toxin-mediated as triggers of immune responses and as toxin-like virulence interference with host integrity triggers plant immunity-associated factors (11). The broad taxonomic distribution of NLPs, in responses. Phytotoxin-induced cellular damage-associated activa- particular their occurrence in both prokaryotic and eukaryotic tion of plant defenses is reminiscent of microbial toxin-induced species, is quite unusual for known microbial phytotoxins, the production of which is restricted to a narrow range of microbial inflammasome activation in vertebrates and may thus constitute PLANT BIOLOGY another conserved element in animal and plant innate immunity. species (6, 8). Major open questions regarding the biological activities of crystal structure ͉ immunity ͉ pathogen ͉ plant immunity ͉ phytotoxin NLPs are as to whether (i) NLPs from various microbial origins are functionally conserved, orthologous proteins; (ii) the ne- illions of years of coevolution of plants and microbial crotic activities of NLP proteins contribute to microbial viru- Mpathogens have shaped both the abilities of microbial lence and infection; and (iii) the necrotic and defense- pathogens to overcome plant disease resistance and the abilities stimulating activities of NLP proteins are mechanistically linked. of plants to cope with microbial invasion (1). Phytopathogens To address these questions, NLPPya from the phytopathogenic from different taxonomic origins secrete structurally unrelated effectors into the apoplast and cytoplasm of plants to establish Author contributions: F.B., H.U.S., T.N., and C. Oecking designed research; C. Ottmann, B.L., infection and to suppress host defenses (2–4). In addition, I.K., M.W., and C. Oecking performed research; W.K., L.M., M.P., and G.A. contributed new phytopathogenic micro-organisms produce a wide range of reagents/analytic tools; C. Ottmann, B.L., I.K., W.K., F.B., M.W., H.U.S., T.N., and C. Oecking cytolytic toxins that function as key virulence determinants (5, analyzed data; and C. Ottmann, F.B., H.U.S., T.N., and C. Oecking wrote the paper. 6). In particular, micro-organisms preferring hemibiotrophic or The authors declare no conflict of interest. necrotrophic lifestyles produce host-selective and host- This article is a PNAS Direct Submission. nonselective toxins that contribute to microbial virulence by Freely available online through the PNAS open access option. facilitating the killing of plant tissues (6–8). Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, Microbial pattern recognition is a prerequisite for the initia- www.pdb.org (PDB ID code 3GNU). tion of antimicrobial defenses in all multicellular organisms, 1C. Ottmann, B.L., and I.K. contributed equally to this work. including plants. The bipartite plant immune system is based 2Present address: Gregor Mendel Institute, A-1030 Vienna, Austria. upon recognition of pathogen-associated molecular patterns by 3To whom correspondence may be addressed. E-mail: claudia.oecking@zmbp. pattern-recognition receptors (1, 9) as well as upon the activities uni-tuebingen.de, [email protected], or [email protected]. of resistance proteins that have evolved to recognize the pres- This article contains supporting information online at www.pnas.org/cgi/content/full/ ence or activities of microbial effectors (2). In addition to the 0902362106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0902362106 PNAS ͉ June 23, 2009 ͉ vol. 106 ͉ no. 25 ͉ 10359–10364 Downloaded by guest on September 27, 2021 Fig. 1. Crystal structure of NLPPya. Secondary structure elements are shown in blue (helices) and green (␤-strands)(A–C). The bound magnesium atom is shown as a blue sphere (A, D–F). Residues involved in ion binding (sticks in E and F) or formation of the disulfide bond (sticks in A and F) are labeled. (A–C) Ribbon plot of NLPPya (A), the actinoporin, sticholysin (B), and the lectin, ABL (C). NGA, N-acetylgalactosamine; POC, phosphorylcholine. (D) Electrostatic surface of NLPPya with a color scale that varies from blue to red, representing positive and negative potential, respectively. (E) Electron density for the bound magnesium and its coordinating residues in NLPPya. The 2Fo-Fc density map (contoured at 1 ␴) is shown in black. (F) Comparison of NLPPya (orange) with modeled structures of NLPPp (blue) and NLPPcc (green). oomycete Pythium aphanidermatum (14) was selected for tertiary produced by sea anemones (Actinia equina equinatoxin II, structure studies. Stichodactyla helianthus sticholysin) (20–22) are most similar to NLPPya (see Fig. 1 A–C). Like NLPPya, these proteins are small, Results single-domain polypeptides exhibiting a central ␤-sandwich ar- The NLP Fold Is Highly Conserved and Is Distantly Related to Cytolytic chitecture surrounded by helices. Superimposition of actino- Actinoporins. Recombinant NLPPya (lacking the N-terminal sig- porins and lectins suggests a high degree of structural similarity nal peptide for secretion) [supporting information (SI) Fig. S1] (score 10.0–10.8), whereas NLPPya represents a more distantly was produced in Escherichia coli, purified under denaturing related protein (see Table S3). Actinoporins and lectins are conditions and reconstituted into its biologically active form soluble proteins that target specific components of membrane (15). The refolded protein crystallized in orthorhombic crystals bilayers via a surface-exposed cavity (see Fig. 1 B and C and Fig. whose structure was solved at a resolution of 1.35 Å. The S2). Moreover, actinoporins are cytolytic toxins that form trans- corresponding crystal structure (crystallography statistics given membrane pores via their
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