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Biosynthesis and Secretion of the Microbial Sulfated Peptide Raxx and Binding to the Rice XA21 Immune Receptor

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Biosynthesis and Secretion of the Microbial Sulfated Peptide Raxx and Binding to the Rice XA21 Immune Receptor Biosynthesis and secretion of the microbial sulfated peptide RaxX and binding to the rice XA21 immune receptor Dee Dee Luua,b,1, Anna Joea,b,c,1, Yan Chend, Katarzyna Paryse, Ofir Bahara,b,2, Rory Pruitta,b,3, Leanne Jade G. Chand, Christopher J. Petzoldd, Kelsey Longa,b, Clifford Adamchaka,b, Valley Stewartf, Youssef Belkhadire, and Pamela C. Ronalda,b,c,4 aDepartment of Plant Pathology, University of California, Davis, CA 95616; bThe Genome Center, University of California, Davis, CA 95616; cFeedstocks Division, Joint Bioenergy Institute, Emeryville, CA 94608; dTechnology Division, Joint Bioenergy Institute, Emeryville, CA 94608; eGregor Mendel Institute, Austrian Academy of Sciences, 1030 Vienna, Austria; and fDepartment of Microbiology & Molecular Genetics, University of California, Davis, CA 95616 Edited by Jonathan D. G. Jones, The Sainsbury Laboratory, Norwich, United Kingdom, and approved March 7, 2019 (received for review October 24, 2018) The rice immune receptor XA21 is activated by the sulfated micro- to Xoo strains lacking RaxX (7–10). Xoo strains lacking RaxX are bial peptide required for activation of XA21-mediated immunity X also compromised in virulence of rice plants lacking XA21 (10). (RaxX) produced by Xanthomonas oryzae pv. oryzae (Xoo). Muta- These results suggest a role for RaxX in bacterial virulence. tional studies and targeted proteomics revealed that the RaxX pre- Tyrosine sulfated RaxX16, a 16-residue synthetic peptide de- cursor peptide (proRaxX) is processed and secreted by the protease/ rived from residues 40–55 of the 60-residue RaxX precursor transporter RaxB, the function of which can be partially fulfilled by peptide (proRaxX), is the shortest characterized immunogenic a noncognate peptidase-containing transporter component B derivative of RaxX (10). RaxX16 shares a 13-residue sequence (PctB). proRaxX is cleaved at a Gly–Gly motif, yielding a mature peptide that retains the necessary elements for RaxX function as with high similarity to the 18-residue plant peptide containing an immunogen and host peptide hormone mimic. These results sulfated tyrosine (PSY1) hormone (10). PSY1 promotes cellular indicate that RaxX is a prokaryotic member of a previously unclas- proliferation and expansion in planta (12) and increases root sified and understudied group of eukaryotic tyrosine sulfated ribo- growth in both Arabidopsis and rice (10). Exogenous application of MICROBIOLOGY somally synthesized, posttranslationally modified peptides (RiPPs). sulfated RaxX16 also promotes root growth (10), which is consis- We further demonstrate that sulfated RaxX directly binds XA21 with tent with the hypothesis that RaxX mimics host PSY1 and PSY1- high affinity. This work reveals a complete, previously uncharacterized like proteins. These observations indicate that RaxX16 contains biological process: bacterial RiPP biosynthesis, secretion, binding to a the biologically active domain of RaxX. eukaryotic receptor, and triggering of a robust host immune response. In Arabidopsis, PSY1 is ribosomally synthesized as a 75-residue propeptide and proteolytically processed into the mature se- peptidase | ABC transporter | RIPP | sulfation | immunogen creted 18-residue sulfated and glycosylated peptide (12). Based on similarities between PSY1 and RaxX16, we hypothesized that ibosomally synthesized and posttranslationally modified pep- Rtides (RiPPs) include antimicrobial, anticancer, insecticidal, and quorum sensing peptides (1). RiPPs are structurally and Significance functionally diverse but share commonalities. They are ribosomally synthesized as a precursor peptide (propeptide) with a cleavable Despite the importance of immune receptors in the biology of N-terminal leader and a posttranslationally modified core that plants and animals, the precise biochemical mechanisms lead- becomes the final secreted bioactive RiPP (Fig. 1A)(1–3). ing to the biosynthesis and secretion of the peptide activators RiPPs achieve substantial chemical diversity through extensive of these immune receptors remain unexplored. Here, we de- posttranslational modifications and are divided into over 20 groups scribe the biosynthesis, processing, and secretion of a peptide (1). RiPPs that have not been well studied or formally categorized activator that binds a rice immune receptor. Our studies also aretyrosinesulfatedpeptides. reveal that this peptide activator is a member of an important Tyrosine sulfation is a posttranslational modification that influ- class of peptides present in both eukaryotic and prokaryotic ences receptor–ligand binding in diverse host–microbe interactions species. Thus, these results provide a major advance in our (4). For example, in humans, tyrosine sulfation of the integral knowledge of the biology of peptide ligands. membrane protein C-C chemokine receptor type 5 (CCR5) sig- nificantly enhances binding of the HIV envelope glycoprotein, Author contributions: D.D.L., A.J., Y.C., K.P., O.B., R.P., L.J.G.C., C.J.P., V.S., Y.B., and P.C.R. designed research; D.D.L., A.J., Y.C., K.P., R.P., L.J.G.C., K.L., and C.A. performed research; facilitating HIV entry (5). Y.B. and P.C.R. contributed new reagents/analytic tools; D.D.L., A.J., Y.C., K.P., R.P., In rice, the transmembrane immune receptor XA21, which shares L.J.G.C., V.S., Y.B., and P.C.R. analyzed data; and D.D.L., A.J., V.S., and P.C.R. wrote similarities to animal Toll-like receptors and the Arabidopsis the paper. flagellin-sensitive 2 and EF-Tu receptors (6), responds to sul- The authors declare no conflict of interest. fated derivatives of the microbial peptide required for activa- This article is a PNAS Direct Submission. tion of XA21-mediated immunity X (RaxX) produced by the Published under the PNAS license. Gram-negative pathogenic bacterium Xanthomonas oryzae pv. 1D.D.L. and A.J. contributed equally to this work. oryzae Xoo – ( )(7 10). The XA21/RaxX interaction conforms to 2Present address: Department of Plant Pathology and Weed Research, Agricultural Re- the “gene-for-gene relationship” initially described by Flor (11) search Organization, Volcani Center, Rishon LeZion 7528809, Israel. in the 1940s. The rice XA21 immune receptor, which is encoded 3Present address: Department of Plant Biochemistry, University of Tübingen, D-72076 by a specific resistance gene, recognizes Xoo strains that pro- Tübingen, Germany. duce the cognate microbial molecule, RaxX. This recognition leads 4To whom correspondence should be addressed. Email: [email protected]. to a host immune response. Thus, plants lacking the XA21 immune This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. receptor are susceptible to RaxX-producing Xoo strains, and con- 1073/pnas.1818275116/-/DCSupplemental. versely, plants carrying XA21 are unable to recognize and respond www.pnas.org/cgi/doi/10.1073/pnas.1818275116 PNAS Latest Articles | 1of10 Downloaded by guest on September 27, 2021 by XA21. To test if RaxX directly binds to the XA21 immune receptor, we used microscale thermophoresis (MST), an optical tool that analyzes protein and small molecule interactions (15). The MST assays were conducted using XA21ECD (XA21 resi- dues 23–649) with varying concentrations of peptide to measure the dissociation constant (Kd). Because we were unable to purify sufficient levels of Xoo-produced RaxX, we used a synthetic 21- residue derivative (RaxX21: proRaxX residues 35–55), which has previously been shown to activate XA21-mediated immune re- sponses in a sulfation-dependent manner (7). When we titrated ECD RaxX21 in the presence of XA21 , we observed a Kd of ∼205 nM with the nonsulfated form (RaxX21-nY) (Fig. 2). This Kd is 12.5-fold higher than the sulfated form (RaxX21-sY), which had a Kd of ∼16 nM (Fig. 2), indicating that sulfated RaxX binds Fig. 1. Biosynthetic pathways of RiPPs and RaxX. (A) General RiPP bio- XA21 with higher affinity than nonsulfated RaxX. synthetic pathway. The RiPP precursor (propeptide) and biosynthetic pro- Although RaxX shares similarities with PSY1 in both se- teins are ribosomally synthesized. The core, which becomes the final RiPP quence and root growth-promoting activities, synthetic sulfated product, is posttranslationally modified by enzyme(s) encoded in the same PSY1 peptides derived from Arabidopsis and rice fail to activate genomic region. Multiple posttranslational modifications can take place on a XA21-dependent immune responses (10). Consistent with these single propeptide. The N-terminal leader is enzymatically removed by a reports, sulfated PSY1 failed to specifically bind XA21ECD (Fig. protease, and the modified core is exported by a transporter, releasing the 2). These results indicate that RaxX binding to XA21ECD is a mature bioactive RiPP. (B) RaxX biosynthetic pathway. proRaxX is riboso- specific interaction, which is enhanced by sulfation. mally synthesized, and the core is sulfated by the sulfotransferase RaxST encoded upstream. We hypothesize that the PCAT RaxB removes the N- terminal leader and transports the sulfated mature RaxX peptide through Selected Reaction Monitoring MS Detects RaxX as a Secreted Mature the T1SS composed of RaxB, the periplasmic adaptor protein RaxA, and the Peptide. Based on its similarity to PSY1 and its direct binding to ECD genetically unlinked outer membrane protein RaxC. XA21 , we hypothesized that sulfated RaxX interacts with host receptors as a secreted proteolytically processed, mature peptide. To test this hypothesis, we assessed the presence of secreted RaxX sulfated proRaxX is also processed
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