Plants, like all organisms, must invest their resources carefully. Growing new roots or shoots may allow a plant to better exploit its environment. But a plant should never leave itself vulnerable to disease. As such, there must be a balance between allocating resources to growth or to defense.

Brassicas like cabbage, Brussels sprouts and wasabi use unique compounds called glucosinolates to protect themselves against pests and disease-causing microbes. These same compounds give these vegetables their distinctive flavors, and they are the source of many of the health benefits linked to eating these vegetables. Yet it was not known if glucosinolates could also affect a plant’s growth and development.

Malinovsky et al. tested a number of purified glucosinolates with the model plant Arabidopsis thaliana, and found that one (called 3-hydroxypropylglucosinolate) caused the plants to grow with stunted roots. When 10 other species of plant were grown with this glucosinolate, almost all had shorter-than-normal roots. The effect was not limited to plants; baker’s yeast also grew less when its liquid media contained the plant-derived compound.

The reason glucosinolates can protect plants against insect pests, provide us with health benefits, and widely inhibit growth is most likely because they have evolved to interact with proteins that are found in many different organisms.Indeed, through experiments with mutant Arabidopsis plants, Malinovsky et al. revealed that their glucosinolate influences the TOR complex. This complex of proteins works in an ancient and widespread signaling pathway that balances growth and development with the available energy and nutrients in organisms ranging from humans to yeast to plants.

The TOR complex plays such a vital role in living cells that problems with this complex have been linked to diseases such as cancer and heart disease. Importantly, the chemical structure of this glucosinolate is unlike other compounds that have already been tested against the TOR complex. As such, it is possible that this glucosinolate might lead to new drugs for a range of human diseases. Further, as this compound affects plant growth, it could also act as a starting point for new herbicides.

Together these findings show how studying molecules made in model organisms and understanding how they function can lead to the identification of new compounds and targets with an unexpectedly wide range of potential uses.

Herbivory, pathogen attacks and weather fluctuations are just some of the factors that constantly fluctuate within a plants environment. To optimize fitness under this wide range of conditions, plants utilize numerous internal and external signals and associated signaling networks to plastically control metabolism and development (Henriques et al., 2014; Smith and Stitt, 2007; Rexin et al., 2015). This metabolic and developmental plasticity begins at seed germination, where early seedling growth is maintained by heterotrophic metabolism relying solely on nutrients and energy stored in the seed including the embryo. Upon reaching light, the seedling transitions to autotrophy by shifting metabolism to initiate photosynthesis and alters development to maximize photosynthetic capacity (Rexin et al., 2015; Galili et al., 2014). Until light is available, it is vital for the plant to prioritize usage from the maternal energy pool, to ensure the shoot will breach the soil before resources are depleted. Because the time to obtaining light is unpredictable, seedlings that had the ability to measure and accordingly adjust their own metabolism would likely enjoy a selective advantage. In this model, energy availability would an essential cue controlling growth throughout a plant’s life and not solely at early life-stages. On a nearly continuous basis, photo-assimilates, such as glucose and sucrose, are monitored and their internal levels used to determine the growth potential by partitioning just the right amount of sugars between immediate use and storage (Smith and Stitt, 2007).

Illustrating the key nature of metabolite measurement within plants is that glucose, is measured by two separate kinase systems that are oppositely repressed and activated to determine the potential growth capacity, SnRKs1 (sucrose non-fermenting 1 (SNF1)-related protein kinases 1) and the Target of Rapamycin (TOR) kinase (Sheen, 2014). SnRKs1s are evolutionarily conserved kinases that are activated when sugars are limiting (Lastdrager et al., 2014). Arabidopsis thaliana (Arabidopsis) has two catalytic SnRK1-subunits, KIN10 and KIN11 (SNF kinase homolog 10 and 11), that activate vast transcriptional responses to repress energy-consuming processes and promote catabolism (Baena-González, 2010; Crozet et al., 2014; Baena-González et al., 2007). This leads to enhanced survival during periods of energy starvation. Oppositely, the TOR kinase is a central developmental regulator, whose sugar-dependent activity controls a myriad of developmental processes including cell growth, cell-cycle, and cell-wall processes. The TOR pathway functions to modulate growth and metabolism by altering transcription, translation, primary and secondary metabolism, as well as autophagy (Sheen, 2014; Sablowski et al., 2014). The TOR kinase primarily functions in meristematic regions where it promotes meristem proliferation. Within these cell types, TOR measures the sugar content and if the tissue is low in sugar, TOR halts growth, even overruling hormone signals that would otherwise stimulate growth (Xiong et al., 2013). In plants, TOR functions within a conserved complex that includes RAPTOR (regulatory-associated protein of TOR) and LST8 (lethal with sec-13 protein 8) (Henriques et al., 2014). RAPTOR likely functions as an essential substrate-recruiting scaffold enabling TOR substrate phosphorylation (Rexin et al., 2015), and LST8 is a seven WD40 repeats protein with unclear function (Moreau et al., 2012). TOR complex (TORC) activity is positively linked with growth (Rexin et al., 2015) as mutants in any component lead to qualitative or quantitative defects in growth and development and even embryo arrest in strong loss-of-function alleles (Menand et al., 2002; Deprost et al., 2005). Although the energy sensory kinases KIN10/11 and TOR sense opposite energy levels, they govern partially overlapping transcriptional networks, which are intimately connected to glucose-derived energy and metabolite signaling (Sheen, 2014; Baena-González et al., 2007). Having two systems to independently sense sugar shows the importance of measuring internal metabolism. A key pathway controlled by TOR in all eukaryotes is autophagy (Liu and Bassham, 2010; Shibutani and Yoshimori, 2014). In non-stressed conditions, continuous autophagy allows the removal of unwanted cell components like damaged, aggregated or misfolded proteins by vacuolar/lysosomal degradation (Inoue et al., 2006). Under low energy conditions, TORC inhibition leads to an induction of autophagy to free up energy and building blocks, through degradation of cytosolic macromolecules and organelles (Shibutani and Yoshimori, 2014). Autophagy-mediated degradation is facilitated by formation of autophagosomes; double membrane structures that enclose cytoplasmic cargo, and delivers it to the vacuole (Shibutani and Yoshimori, 2014; Feng et al., 2014; Le Bars et al., 2014; Zhuang et al., 2016).

In nature, plant plasticity is not only limited to responding to the internal energy status, but to an array of external environmental inputs. The multitude of abiotic and biotic factors that plants continuously face often require choices between contradictory responses, that requires integrating numerous signals across an array of regulatory levels to create the proper answer. For example; plant defense against biotic organisms requires coordination of metabolic flux to defense and development while in continuous interaction with another organisms and the potential for interaction with other organisms. A proper defense response is vital for the plant as a metabolic defense response to one organism can impart an ecological cost by making the plant more sensitive to a different organism (Züst et al., 2012). Therefore, a plant must choose the most appropriate defense response for each situation to optimize its fitness and properly coordinate its defense response with growth and development. A key defense mechanism intricately coordinated across development is the synthesis of specific bioactive metabolites that are often produced in discrete tissues at specific times. A current model is that developmental decisions hierarchically regulate defense metabolism with little to no feed-back from defense metabolism to development. However, work on the glucosinolate and phenolic pathways is beginning to suggest that defense metabolites can equally modulate development (Katz et al., 2015; Bonawitz et al., 2012; Bonawitz et al., 2014; Kim et al., 2014; Francisco et al., 2016a; Francisco et al., 2016b), thus suggesting that development and defense metabolism can directly cross-talk.

To asses if and how defense metabolites can signal developmental changes, we chose to investigate the glucosinolate (GSL) defense metabolites. The evolution of the core of GSL biosynthesis is relatively young, and specifically modified GSL structures are even more recent (Sønderby et al., 2010). There are >120 known GSL structures limited to plants from the Brassicales order and some Euphorbiaceae family members, with Arabidopsis containing at least 40 structures (Sønderby et al., 2010). GSLs are amino acid derived defense metabolites that, after conversion to an array of bioactive compounds, provide resistance against a broad suite of biotic attackers (Sønderby et al., 2010; Lambrix et al., 2001; Kliebenstein et al., 2002). GSLs not only exhibit a wide structural diversity, but their composition varies depending on environmental stimuli, developmental stage and even across tissues. This, combined with the information-rich side chain, makes GSLs not only an adaptable defense system, but also prime candidates for having distinctive signaling functions. Previous work has suggested that there may be multiple signaling roles within the GSLs (Francisco et al., 2016a; Francisco et al., 2016b; Clay et al., 2009; Khokon et al., 2011; Bednarek et al., 2009). Tryptophan-derived indole GSLs or their breakdown products alter defense responses to non-host pathogens illustrated by biosynthetic mutants devoid of indole GSLs being unable to deposit PAMP-induced callose in cell walls via an unknown signal and pathway (Clay et al., 2009; Bednarek et al., 2009). Similarly, indole GSL activation products have the ability to directly alter auxin perception by interacting with the TIR1 auxin receptor (Katz et al., 2015). In contrast to indole GSLs, mutants in aliphatic GSL accumulation alter flowering time and circadian clock oscillations (Kerwin et al., 2011; Jensen et al., 2015). The aliphatic GSL activation product, allyl isothiocyanate can induce stomatal closure but it is unknown if this is specific to allylGSL or a broader GSL property (Khokon et al., 2011; Boller and Felix, 2009). AllylGSL (other names are 2-propenylGSL and sinigrin) can also alter plant biomass and metabolism in Arabidopsis (Francisco et al., 2016a; Francisco et al., 2016b). While these studies have provided hints that the GSL may have signaling potential, there is little understanding of the underlying mechanism or the structural specificity of the signal. To explore whether built-in signaling properties are a common attribute of GSLs, we screened for altered plant growth and development in the presence of specific purified aliphatic GSLs. In particular, we were interested in identifying candidate signals whose activity could ensure fast repartitioning of resources between development and defense. Here we present a novel signaling capacity specific to the aliphatic 3-hydroxypropylglucosinolate (3OHPGSL). Our results suggest that 3OHPGSL signaling involves the universally conserved TOR pathway for growth and development, as mutants in TORC and autophagy pathways alter responsiveness to 3OHPGSL application.

In this study we describe a novel signaling capacity associated with 3OHPGSL, a defense metabolite present in Arabidopsis, and provide evidence that the linked signal proceeds via the TOR pathway. Application of exogenous 3OHPGSL caused reversible root meristem inhibition by morphological reprogramming of the root zones, i.e. dramatically reduced the root meristem size and limited root cell elongation (Figure 4). This response occurred at levels within the endogenous range and there was no evidence of cell death in any treated root, suggesting that this is not a toxicity response (Figure 1). Additionally, these morphological responses were specific to 3OHPGSL and not caused by any structurally or biosynthetically related GSL, suggesting that these responses were not because of generic properties shared by GSLs (Figure 2). Exposing a wide phylogenetic array of plants, including lineages that have never produced GSLs, to 3OHPGSL showed that application of this compound can inhibit growth broadly across the plant kingdom as well as in yeast (Figure 3, Figure 3—figure supplement 1). This suggests conservation of the downstream signaling pathway across these diverse plant lineages. Equally, if the signaling compound is not 3OHPGSL itself, but a derivative, then the required biosynthetic processes must be conserved. This conservation largely rules out the specific GSL activation pathway controlled by Brassicales specific thioglucosidases, myrosinases (Barth and Jander, 2006; Nakano et al., 2017; Bones and Rossiter, 2006). The phylogenetic conservation of the 3OHPGSL response led us to search for a target pathway controlling growth and development that would be evolutionary well conserved between the tested species.

By comparing the root phenotype identified with 3OHPGSL application to the published literature, we hypothesized that 3OHPGSL treatment may affect TORC, a key primary metabolic sensor that controls growth and development, and is conserved back to the last common eukaryotic ancestor (Henriques et al., 2014). Active site TOR inhibitors inhibit root growth in numerous plant species similar to 3OHPGSL application (Montané and Menand, 2013), supporting the hypothesis that 3OHPGSL may function via TORC. A model with 3OHPGSL affecting TORC would explain how 3OHPGSL can alter root development across the plant kingdom (Figure 3). Mechanistic support for this hypothesis came from a number of avenues. First, 3OHPGSL can block the TOR-mediated sugar activation of arrested meristems (Figure 6). Second, the TORox mutant intensifies 3OHPGSL linked signaling (Figure 5), and correspondingly loss-of-function mutants of the substrate binding TORC component raptor2 diminish the 3OHPGSL effect (Figure 5—figure supplement 3). Additionally, there are clear phenotypic overlaps between the root phenotypes induced by known TOR inhibitors and 3OHPGSL, e.g. root inhibition, inhibition of cell elongation, and notably the dramatic reduction of the meristem sizes (Figure 7). Critically, 3OHPGSL and known small-molecule inhibitors of TOR were mutually antagonistic for a number of phenotypes. In pharmacology, the outcomes of a drug combination can either be antagonistic, additive or synergistic, depending on whether the effect is less than, equal to, or greater than the sum of the effects of the two drugs (Jia et al., 2009). Antagonistic interactions, as observed with 3OHPGSL and AZD, can occur if two drugs exhibit mutual interference against the same target site, or if their targets converge on the same regulatory hub (Jia et al., 2009). Together, these lines of evidence suggest that 3OHPGSL or a derived metabolite targets the TOR pathway to alter root meristem development within Arabidopsis and potentially other plant species.

Extending the analysis to pathways downstream of TORC, showed that loss of ATG5, a vital component of the autophagic machinery (Liu and Bassham, 2010; Shibutani and Yoshimori, 2014), intensifies the 3OHPGSL response (Figure 8A-DB). This supports the hypothesis that 3OHPGSL signaling proceeds through the TOR complex, but also suggest that this signal requires parts of the autophagic machinery. Loss of another autophagic component, ATG2, did not influence the 3OHP response (Figure 8C–D). Together, this raises the possibility that 3OHPGSL influenced responses involve predominantly a micro-autophagy pathway, which is ATG5- but may not be ATG2-dependent, rather than the macro-autophagy pathway that depends upon both genes (Ryabovol and Minibayeva, 2016; Li et al., 2012). Micro-autophagy removes captured cytoplasmic components directly at the site of the vacuole via tonoplast invagination. The cargo to be degraded ranges from non-selective fractions of the cytoplasm to entire organelles, dependent on the type of micro-autophagy. The two ubiquitin-like conjugation systems, and thereby ATG5, have been shown to be involved in several forms of micro-autophagy, such as starvation-induced, non-selective, and glucose-induced selective autophagy (Li et al., 2012). Interestingly, micro-autophagy involves vacuolar movement of cargo, and the vacuole is considered the main storage site for glucosinolates (Mikkelsen et al., 2004). Thus, ATG5 may be responsible for enabling the movement of exogenously applied 3OHPGSL out of the cytoplasm where it or a derivative metabolite could interact with the TORC pathway and into the vacuole. This would decrease the concentration of the 3OHPGSL associated signal and could explain why the atg5-1 mutant is more sensitive to 3OHPGSL application. Further work is required to test if ATG5 is functioning to attenuate the 3OHPGSL associated signal.

A conundrum for defense signaling compounds to affect growth is the evolutionary age discrepancy; defense metabolites are typically evolutionarily very young, as they are often species or taxa specific, while growth regulatory pathways are highly conserved across broad sets of plant taxa. This raises the question of which mechanism(s) may allow this connection between young metabolites and old regulatory pathways. This suggests that plants may sense young metabolites using evolutionarily old signaling pathways. Similar evidence is coming from other secondary metabolite systems suggesting that this may be a general phenomenon. For example, an indolic GSL activation product can interact with the conserved TIR1 auxin receptor to alter auxin sensitivity within Arabidopsis (Katz et al., 2015). Similarly, an unknown phenolic metabolite appears to affect regulation of growth and development by influencing the Mediator complex that is conserved across all eukaryotes (Bonawitz et al., 2012; Bonawitz et al., 2014; Kim et al., 2014); and the plant polyphenol resveratrol directly inhibits the mammalian TOR to induce autophagy (Park et al., 2016). Thus, young plant metabolites can influence evolutionarily conserved pathways. Interestingly, this strongly resembles the action of virulence-associated metabolites within plant pathogens. Pseudomonad bacteria produce the evolutionarily young coronatine that alters the plant defense response by interacting with the conserved JA-Ile receptor COI1 (Xie et al., 1998). In plant/pathogen interactions, this ability of pathogen-derived metabolites to alter plant defense signaling is evolutionarily beneficial because it boosts the pathogen’s virulence in planta. It is less clear if this selective pressure model also applies to plant defense compounds that interact with endogenous signaling pathways. Following the plant/pathogen derived model, it is tempting to assume that such plant defense metabolites have been co-selected on their ability to affect the biotic attacker and simultaneously provide information to the plant. However, an alternative hypothesis that is that these examples may simply be serendipitous cases, where the defense metabolites happened to interact with a pathway and are potentially of no evolutionary benefit. In this model, the plant might still be adapting to the evolution of this new regulatory linkage. In the particular case of 3OHPGSL, the AOP3 enzyme that makes this compound evolved prior to the split between A. thaliana and A. lyrata suggesting that these species have had at least several million years/generations of potential to adapt. However, the two hypotheses need to be empirically tested. Central to testing between the two hypotheses is to assess if the observed signaling effects have any fitness benefit for the plant suggesting that even if the connections arose by serendipity that they have been maintained by a selective benefit. This will require field testing the fitness of plants that contrast for the presence of these connections. An alternate way to test between these hypotheses would be to conduct a broad survey of plant metabolites to test how many can affect signaling within the plant. If a large fraction of metabolites have potential signaling function, it is unlikely that all of these are simply serendipitous cases that have not had sufficient time to be removed by natural selection. However; earlier studies have provided evidence that both allyl GSL and the GSL breakdown product indole-3-carbinol affect plant signaling and growth (Katz et al., 2015; Francisco et al., 2016a; Francisco et al., 2016b). In addition, R- and S-2-hydroxybut-3-enyl GSL promoted root growth (Figure 2—figure supplement 1), suggesting that dual effects of defense metabolites such as 3OHPGSL are possibly more general.

Within this report, we provided evidence that 3OHPGSL, or derived compounds, appears to function as a natural endogenous TORC inhibitor that can work across plant lineages. This creates a link whereby the plant’s endogenous defense metabolism can simultaneously coordinate with growth. Such a built-in signaling capacity would allow coordination between development and defense, as the plant could use the defense compound itself as a measure of the local progress of any defense response and readjust development and defense to optimize against the preeminent threat. Future work is required to identify the specific molecular interaction that allows this communication to occur, this will help to illuminate how and why plants measure their own defense metabolism to coordinate available resources more broadly with growth. Future work might also ascertain whether there is a broader class of plant produced TOR inhibitors. If this is true, they might be highly useful in understanding TOR function across kingdoms of life and possibly to reveal significant aspects of this universally conserved pathway that may have gone unnoticed in other eukaryotic models.

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Author details

1. Frederikke Gro Malinovsky

   DynaMo Center, Copenhagen Plant Science Center, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9833-7968

2. Marie-Louise F Thomsen

   DynaMo Center, Copenhagen Plant Science Center, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark

   Contribution

   Formal analysis, Validation, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

3. Sebastian J Nintemann

   DynaMo Center, Copenhagen Plant Science Center, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark

   Contribution

   Investigation, Visualization, Writing—review and editing

   Competing interests

   No competing interests declared

4. Lea Møller Jagd

   DynaMo Center, Copenhagen Plant Science Center, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark

   Contribution

   Investigation, Visualization, Writing—review and editing

   Competing interests

   No competing interests declared

5. Baptiste Bourgine

   DynaMo Center, Copenhagen Plant Science Center, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark

   Present address

   Department of Plant Molecular Biology, University of Lausanne, Lausanne, Switzerland

   Contribution

   Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

6. Meike Burow

   DynaMo Center, Copenhagen Plant Science Center, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark

   Contribution

   Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2350-985X

7. Daniel J Kliebenstein

   1. DynaMo Center, Copenhagen Plant Science Center, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark
   2. Department of Plant Sciences, University of California, Davis, Davis, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   kliebenstein@ucdavis.edu

   Competing interests

   Reviewing editor, eLife

   "This ORCID iD identifies the author of this article:" 0000-0001-5759-3175

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