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RNA-binding proteins contribute to small RNA loading in plant extracellular vesicles

A Publisher Correction to this article was published on 24 March 2021

This article has been updated

Abstract

Plants use extracellular vesicles (EVs) to transport small RNAs (sRNAs) into their fungal pathogens and silence fungal virulence-related genes through a phenomenon called ‘cross-kingdom RNAi’. It remains unknown, however, how sRNAs are selectively loaded into EVs. Here, we identified several RNA-binding proteins in Arabidopsis, including Argonaute 1 (AGO1), RNA helicases (RHs) and annexins (ANNs), which are secreted by exosome-like EVs. AGO1, RH11 and RH37 selectively bind to EV-enriched sRNAs but not to non-EV-associated sRNAs, suggesting that they contribute to the selective loading of sRNAs into EVs. Conversely, ANN1 and ANN2 bind to sRNAs non-specifically. The ago1, rh11rh37 and ann1ann2 mutants showed reduced secretion of sRNAs in EVs, demonstrating that these RNA-binding proteins play an important role in sRNA loading and/or stabilization in EVs. Furthermore, rh11rh37 and ann1ann2 showed increased susceptibility to Botrytis cinerea, suggesting that RH11, RH37, ANN1 and ANN2 positively regulate plant immunity against B. cinerea.

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Fig. 1: RNA-binding proteins present in plant EVs.
Fig. 2: TET8 and PEN1 label different classes of EVs in Arabidopsis.
Fig. 3: TET8-positive EVs are an important subclass of EVs for secretion of sRNAs and RBPs.
Fig. 4: EV-associated RBPs colocalize with EV marker TET8 in isolated EVs.
Fig. 5: EV-secreted RBPs mediate sorting and stabilization of sRNAs into EVs.
Fig. 6: EV-associated RBPs contribute to plant immunity to fungal infection.

Data availability

The data that support the findings of this study are available in the Supplementary Information and Source data provided with this paper or from the corresponding authors upon reasonable request. Additional data related to this study are available from the corresponding author upon request. The raw files for LC–MS/MS analyses generated during this study are available at PeptideAtlas (http://www.peptideatlas.org/PASS/PASS01572).

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Acknowledgements

We thank N. Raikhel for the 35Spro::ARA6-GFP and SYP61pro::CFP-SYP61 seeds, L. Boavida for TET8pro::TET8-GFP and 35Spro::TET8-GFP seeds and R. Hamby for editing the paper. This work was supported by grants from the National Institutes of Health (R01GM093008 and R35GM136379), the National Science Foundation (IOS2017314) and AES-CE (PPA-7517H) to H.J. and the National Institutes of Health (R01 ES025121) to Y.W. Q.C. is supported by funds from National Natural Science Foundation of China (32070288).

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Authors

Contributions

H.J. conceived the idea and supervised the project. B.H., Q.C. and H.J. designed the experiments. B.H. and Q.C. performed most of the experiments and analysed data. L.Q. and T.H. contributed to the functional analysis of the EV-associated RBPs. S.W. generated the ANN2-CFP line and C.H. generated the rh11rh37 double mutant. W.M. and Y.W. performed mass spectrometry and conducted bioinformatics analysis. B.H., Q.C. and H.J. wrote the manuscript.

Corresponding author

Correspondence to Hailing Jin.

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The authors declare no competing interests.

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Peer review information Nature Plants thanks Michael Feldbrügge and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Images show the various steps in plant EVs isolation.

a, Leaves were harvested and rinsed; the petioles were removed. Next, leaves were placed in a syringe with infiltration buffer and vacuumed. b, The leaves were taped in the same orientation onto a 1 ml syringe after infiltration buffer was vacuumed into leaves. c, Syringe with taped leaves was placed into a 50 ml conical tube. d, The apoplastic wash was collected by gently centrifuging the leaves at 900 g at 4 °C. e, Scheme of EV isolation by differential ultracentrifugation from apoplastic wash of Arabidopsis. Sup, Supernatant. f, Confocal microscopy images of P40 and P100 fractions isolation by ultracentrifugation from apoplastic wash of TET8pro:TET8-GFP plants. Equivalent amounts of plants were inoculated with B. cinerea for 36 hours before P40 and P100 fraction isolation. Scale bars, 10 μm. g, GFP-labelled TET8 was detectable in both P40 and P100 EV fractions by western blot. The experiments were repeated three times independently with similar results. Source data are provided as a Source Data file. Source data

Extended Data Fig. 2 Gene ontology (GO) enrichment analysis of proteins enriched in EVs.

a, b, The plant EV proteome from B. cinerea-infected Arabidopsis plants was categorized based on GO terms related to biological process (a) and molecular function (b) through The Arabidopsis Information Resource Web site (www.arabidopsis.org).

Extended Data Fig. 3 TET8 and PEN1 localization.

a, Confocal microscopy images of TET8-YFP and ARA6-CFP at B. cinerea infection site on N. benthamiana. TET8-YFP was partially colocalized with ARA6-CFP signals. b, Fluorescent intensity was quantified for the images used in (a). Transections used for fluorescence intensity measurements are indicated by blue lines. Green and red lines represent histograms of ARA6-CFP and TET8-YFP fluorescent intensities, respectively. c, Confocal microscopy images of CFP-PEN1 and ARA6-YFP at the B. cinerea infection site on N. benthamiana. CFP-PEN1 did not colocalize with ARA6-YFP signals. d, Fluorescence intensity was quantified for the images used in (c). Transections used for fluorescence intensity measurements are indicated by blue lines. Green and red lines represent histograms of CFP-PEN1 and ARA6-YFP fluorescent intensities, respectively. Scale bars, 10 μm.

Extended Data Fig. 4 Bottom-loading EV separation by sucrose gradient centrifugation.

a, Pellets obtained from 100,000 g centrifugations (P100) were used to perform sucrose gradient centrifugation by both top and bottom loading. b, Six fractions were collected from bottom-loading plant EV sucrose gradient centrifugation. TET8, AGO1, RH11, RH37, ANN1, ANN2 were detected by western blot. EV-enriched (TAS1c-siR483, TAS2-siR453 and miR166) and non-EV-associated (TAS1c-siR585 and TAS2-siR710) sRNAs were detected by RT–PCR. The experiments were repeated three times independently with similar results. Source data are provided as a Source Data file. Source data

Extended Data Fig. 5 Colocalization between EV-associated RBPs with MVB marker ARA6 and EV marker TET8.

a, b, Fluorescent protein-labelled RBPs were co-expressed transiently with MVB marker ARA6 (a) and EV marker TET8 (b) in N. benthamiana. Confocal microscopy was used to determine the localization of RBPs (AGO1, RH11, RH37, ANN1, ANN2) with ARA6 and TET8. AGO2 was used as a control. Scale bars, 10 μm. The experiments were repeated three times independently with similar results.

Extended Data Fig. 6 sRNAs specifically bound by AGO2, AGO4 and AGO5 were absent from plant EVs.

AGO2-associated miR393*, AGO4-associated siR1003, AGO5-associated miR390* and both AGO1 and AGO5-associated miR156 were examined in isolated plant EVs by sRNA RT–PCR. TAS1c-siR483, TAS2-siR453 and miR166 were detected in EVs and used as positive controls. TAS1c-siR585 and TAS2-siR710 were used as negative controls. The experiments were repeated three times independently with similar results. Source data are provided as a Source Data file. Source data

Extended Data Fig. 7 AGO1 and RH37 selectively bind EV-enriched sRNAs in N. benthamiana.

YFP-AGO1 or RH37-CFP were co-expressed with EV-enriched (TAS1c-siR483, TAS2-siR453 and miR166) and non-EV-associated sRNAs (TAS1c-siR585 and TAS2-siR710) in N. benthamiana, sRNAs were immunoprecipitated from plant total extraction using antibodies against GFP and detected by sRNA RT–PCR. IgG was used as a negative control. The experiments were repeated three times independently with similar results. Source data are provided as a Source Data file. Source data

Extended Data Fig. 8 Verification of rh11rh37 and ann1ann2 double mutants.

a, The developmental phenotypes of the rh11rh37 double mutant that both RH11 and RH37 expression was suppressed by artificial miRNA in Col-0. b, The real-time RT–PCR analysis of RH11 and RH37 expression in rh11rh37 mutants. The data are presented as mean ± s.d., n = 3 biologically independent replicates. The error bars indicate the standard deviation (s.d.). c, The developmental phenotypes of the rh11rh37#6 mutant that RH37 expression was suppressed by artificial miRNA in rh11 knockout mutant. d, RT–PCR analysis of RH11 and real-time PCR analysis of RH37 in rh11rh37#6 mutant. The data are presented as mean ± s.d., n = 3 biologically independent replicates. The error bars indicate the standard deviation (s.d.). e, Phenotype of wild-type and ann1ann2 mutant grown for 4 weeks in a growth chamber. f, RT–PCR analysis of the expression levels of ANN1 and ANN2 in wild-type and ann1ann2 double mutant. The statistical analysis in b was performed using ANOVA Dunnett’s multiple comparisons test. The statistical analysis in d was performed using unpaired two-tailed Student’s t-tests. The small open circles represent the individual values. The asterisks indicate significant differences: *P < 0.05, **P < 0.01, ***P < 0.001. The experiments were repeated three times independently with similar results. Source data are provided as a Source Data file. Source data

Extended Data Fig. 9 EV-enriched sRNA amount was reduced in EVs isolated from the mutants of EV-associated RBPs.

The relative level of both EV-enriched and non-EV-associated sRNAs were examined by quantitative real-time RT–PCR in the total fraction and EV fraction from ago1-27 (a), rh11rh37 (b) and ann1ann2 (c) mutants. The data are presented as mean ± s.d., n = 3 biologically independent replicates. The error bars indicate the standard deviation (s.d.). The statistical analysis was performed using unpaired two-tailed Student’s t-tests. The small open circles represent the individual values. The asterisks indicate significant differences: **P < 0.01, ***P < 0.01, NS, not significant. Source data

Supplementary information

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Supplementary Information

Supplementary Tables 1–3.

Source data

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He, B., Cai, Q., Qiao, L. et al. RNA-binding proteins contribute to small RNA loading in plant extracellular vesicles. Nat. Plants 7, 342–352 (2021). https://doi.org/10.1038/s41477-021-00863-8

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