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- American Society for Biochemistry and Molecular Biology
- Copyright
- Copyright © 2020 Elsevier Inc.
- ISSN
- 0021-9258
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- 1083-351X
- DOI
- 10.1074/jbc.rev120.010854
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Abstract
cro REVIEWS Published, Papers in Press, April 24, 2020, DOI 10.1074/jbc.REV120.010854 Brad M. Binder* X From the Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA Edited by Joseph M. Jez Ethylene is a gaseous phytohormone and the first of this hor- ethylene-signaling pathway was predominantly delineated with mone class to be discovered. It is the simplest olefin gas and is research on Arabidopsis thaliana and is comprised of a combi- biosynthesized by plants to regulate plant development, growth, nation of components that is not found in other pathways. This and stress responses via a well-studied signaling pathway. One review will mainly focus on this research using Arabidopsis. of the earliest reported responses to ethylene is the triple However, it is worth pointing out that similar signaling path- response. This response is common in eudicot seedlings grown ways occur in diverse plants (4–11) so that information from in the dark and is characterized by reduced growth of the root Arabidopsis about ethylene signaling is usually applicable to and hypocotyl, an exaggerated apical hook, and a thickening of other species. the hypocotyl. This proved a useful assay for genetic screens and Early molecular genetic studies uncovered several key com- enabled the identification of many components of the ethylene- ponents for ethylene signaling, including a family of receptors; signaling pathway. These components include a family of ethyl- the CTR1 protein kinase; EIN2, which is a transmembrane pro- ene receptors in the membrane of the endoplasmic reticulum tein of unknown biochemical activity; and transcription factors, (ER); a protein kinase, called constitutive triple response 1 such as EIN3, EILs, and ERFs. This led to a linear, genetic model (CTR1); an ER-localized transmembrane protein of unknown where, in the absence of ethylene, the receptors activate CTR1, biochemical activity, called ethylene-insensitive 2 (EIN2); and which negatively regulates downstream signaling (Fig. 1). Eth- transcription factors such as EIN3, EIN3-like (EIL), and ethyl- ylene functions as an inverse agonist by inhibiting the recep- ene response factors (ERFs). These studies led to a linear model, tors, leading to release of inhibition by CTR1, resulting in eth- according to which in the absence of ethylene, its cognate recep- ylene responses (12). This genetic model provided a general tors signal to CTR1, which inhibits EIN2 and prevents down- framework that has been refined with further research, result- stream signaling. Ethylene acts as an inverse agonist by inhibit- ing in a more complete and detailed model for ethylene signal- ing its receptors, resulting in lower CTR1 activity, which ing, including surprising cases of cross-talk from the receptors releases EIN2 inhibition. EIN2 alters transcription and transla- to other signaling pathways, details for how a signal perceived at tion, leading to most ethylene responses. Although this canoni- the ER membrane affects transcription in the nucleus, and mul- cal pathway is the predominant signaling cascade, alternative tiple roles for EIN2. Details from this research have led to var- pathways also affect ethylene responses. This review summa- ious ways to control ethylene signaling. Most of these controls rizes our current understanding of ethylene signaling, including are geared toward inhibiting ethylene responses to prevent these alternative pathways, and discusses how ethylene signal- post-harvest spoilage. However, there is also a need for stimu- ing has been manipulated for agricultural and horticultural lating ethylene responses, such as to cause premature germina- applications. tion of parasitic plants so that fields can be cleared of these problematic plants. These discoveries and applications will be summarized in this review. Ethylene (IUPAC name ethene) is the simplest olefin gas and was the first gaseous molecule shown to function as a hormone Ethylene-signaling components and the canonical (1). It is biosynthesized by plants and is well-known to affect pathway various developmental processes, such as seed germination, The first step in ethylene perception is the binding of ethyl- fruit ripening, senescence, and abscission, as well as responses ene to receptors. Ethylene receptors have homology to bacterial to various stresses, such as flooding, high salt, and soil compac- two-component receptors that signal via autophosphorylation tion (2, 3). The ethylene signal transduction pathway has been on a histidine residue followed by phosphotransfer to an aspar- extensively studied, in part because ethylene affects so many tate residue in the receiver domain of a response regulator pro- traits related to plant vigor and post-harvest physiology and tein (13). Ethylene receptors, as well as other two-component- storage. like receptors, such as the phytochromes and cytokinin Once biosynthesized, ethylene diffuses throughout the receptors, are believed to have been acquired by plants from the plant and binds to ethylene receptors to stimulate ethylene cyanobacterium that gave rise to chloroplasts (14–18). Data responses. It can also diffuse to surrounding plants and is the from a recent phylogenetic analysis suggest a common origin basis of the saying one bad apple spoils the bunch, where ethyl- for the ethylene-binding domain in cyanobacteria and plants ene produced by an apple hastens the ripening of bananas. The (19). It is thus interesting to note that ethylene binding has been observed in diverse cyanobacteria, and at least one cyanobacte- * For correspondence: Brad M. Binder, [email protected]. rium, Synechocystis, has a functional ethylene receptor that reg- This is an Open Access article under the CC BY license. 7710 J. Biol. Chem. (2020) 295(22) 7710 –7725 © 2020 Binder. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. JBC REVIEWS: Ethylene signaling Figure 1. Simple genetic model of ethylene signaling. In black is shown a model for ethylene signaling based on molecular genetic experiments in Arabidopsis. These experiments showed that ethylene signaling involves ethylene receptors (ETR1, ERS1, ETR2, EIN4, and ERS2), the protein kinase CTR1, and EIN2 that signals to the transcription factors EIN3, EIL1, and EIL2. These, in turn, signal to other transcription factors, such as the ERFs, leading to ethylene responses. This has long been considered the canonical signaling pathway. In this model, CTR1 is a negative regulator of signaling. Ethylene functions as an inverse agonist, where it inhibits the receptors, which leads to lower activity of CTR1 releasing downstream components from inhibition by CTR1. More recent evidence has shown the existence of an alternative, “noncanonical” pathway (in gray), where ETR1 signals to histidine-containing AHPs and then to ARRs to modulate responses to ethylene. ulates cell surface properties to affect biofilm formation and phototaxis (20–22). Additionally, ethylene-binding affinities to some of these cyanobacteria and the heterologously expressed Synechocystis ethylene receptor are similar to what has been observed in plants (23), showing a conservation of this domain between these organisms. However, the organism where ethyl- ene receptors first arose remains unknown. The observation that genes encoding for proteins with putative ethylene-bind- ing domains are found in other phyla of bacteria (22) will make answering this question difficult. By contrast, as will be discussed in more detail below, even though some of the plant ethylene receptor isoforms have retained histidine kinase activity, this activity is not crucial for ethylene perception. This is in contrast to the one cyanobacte- rial system so far characterized where phosphotransfer is cen- tral to the function of the receptor (22, 24, 25). Additionally, Figure 2. Diagram of domains of receptor isoforms. The receptors are some plant ethylene receptor isoforms have serine/threonine dimers located in the ER membrane. Each dimer is stabilized by two disulfide kinase activity, indicating that the outputs of these receptors in bonds near the N terminus. All of the receptors contain transmembrane heli- ces that comprise the ethylene-binding domain followed by a GAF and kinase plants are now diverged from the ancestral proteins. Recent domain. ETR1 is a histidine kinase, and the other four isoforms are serine/ reviews present more information about ethylene receptors in threonine kinases. Three of the five contain a receiver domain at the C termi- nus of the protein. The models for the receptors are based on published nonplant species (26, 27). structural and computational studies on ETR1 (43, 69), where each monomer Plants contain multiple ethylene receptor isoforms. Early coordinates a copper ion required for ethylene binding. In ETR1, the DHp studies identified ethylene-binding sites in the ER membranes domain of the kinase dimerizes, and a flexible region allows each kinase cat- alytic domain to associate with the DHp domain. It is unknown whether the of plants (28, 29), and subsequent research on specific receptor kinase domains of the other isoforms also dimerize. The receiver domains are isoforms from various plants confirmed that ethylene receptors predicted to be orientated away from the central axis of the receptor dimer. are localized to the ER (30–35). In Arabidopsis, five isoforms have been identified and are referred to as ethylene response 1 at the N terminus that are unknown in function. The receptors (ETR1), ethylene response sensor 1 (ERS1), ETR2, ERS2, and can be further distinguished by their kinase activity. ETR1 has EIN4 (36–40). Mutations in any one of these receptors that histidine kinase activity, whereas ETR2, ERS2, and EIN4 have prevent ethylene binding lead to an ethylene-insensitive plant serine/threonine kinase activity, and ERS1 has been docu- (12, 20, 36, 37, 41). There are also some mutations in these mented to have both, depending on assay conditions, although receptors that have no effect on ethylene binding but prevent it is believed to be a serine/threonine kinase in vivo (44, 45). signaling through the receptor, which also leads to ethylene The receptors form homodimers that are stabilized at their N insensitivity (20). termini by two disulfide bonds (46–48). Nevertheless, these The different receptor isoforms in plants have similar disulfide bonds are necessary neither for binding of ethylene to domain architecture (Fig. 2) with three transmembrane -heli- ETR1 (48) nor for a functional ETR1 receptor in planta (49). In ces at the N terminus, which comprises the ethylene-binding ETR1, it is thought that dimerization between monomers also domain, followed by a GAF (cGMP-specific phosphodies- occurs between the dimerization and histidine phosphotrans- terases, adenylyl cyclases, and FhlA) and kinase domain. Three fer (DHp) domains of each kinase domain (43). It is unclear of the five receptors also contain a receiver domain that is sim- whether dimerization between kinase domains of the other ilar to what is found in bacterial two-component receptors (42, receptor isoforms occurs. It has also been suggested that het- 43). The receptors fall into two subfamilies with ETR1 and erodimers are possible (35, 50). Evidence that these are recep- ERS1 in subfamily 1 and the other three isoforms in subfamily 2 tors is that all of these proteins bind ethylene with high affinity (20). The subfamily 2 receptors contain additional amino acids (41, 47, 51, 52), and specific mutations in any one of these pro- J. Biol. Chem. (2020) 295(22) 7710 –7725 7711 JBC REVIEWS: Ethylene signaling teins lead to ethylene insensitivity (36, 38–40, 53). Similar pro- to be coordinated by amino acids in helices 1 and 2 of each teins from tomato also bind ethylene with high affinity and monomer (69). when mutated lead to ethylene insensitivity (51, 54–56). The biochemical output of the receptors has yet to be deter- Ethylene binds to the N-terminal, transmembrane portion of mined. The GAF, kinase, and receiver domains are the likely heterologously expressed receptors with K values reported in output domains, but the specifics of how ethylene signal is the nanomolar range (21, 41, 52), which corresponds to ethyl- transduced are unknown. This is complicated by research ene-binding affinities reported in plants (57–64). One differ- showing that even though the receptors have overlapping roles ence between heterologously expressed receptors and those in for many traits, for specific traits or under specific conditions, planta is that ethylene dissociates from the former with a single, individual receptor isoforms have a role, whereas others do not slow rate having a half-time of release of 10–12 h (41, 51, 52), (52, 79–87). In some cases, individual isoforms display opposite whereas there are two rate constants of release in planta (64, roles from other isoforms. For instance, ETR1 is necessary and 65). In planta, there is an initial, rapid release of ethylene in the sufficient for ethylene-stimulated nutational bending of hypo- first 30 min after ethylene removal, followed by slow release cotyls in dark-grown Arabidopsis seedlings, whereas the other with similar kinetics to the heterologously expressed receptors. four receptor isoforms inhibit this response (80, 86). Also, loss Because ethylene can enhance the proteolysis of ethylene of ETR1, and to a lesser extent EIN4, results in plants that are receptors (31, 66, 67), this rapid release of ethylene from recep- less sensitive to the plant hormone abscisic acid (ABA) during tors in plants is likely due to proteolysis of the ethylene-bound seed germination, whereas loss of ETR2 causes plants to be receptors. more sensitive to ABA (83, 85). There is recent evidence that The cytosolic domains of ETR1 have been structurally char- ETR1 and ETR2 are signaling independently of CTR1 to cause acterized (42, 43, 68). This has led to a model of the ETR1 dimer the changes in ABA responsiveness, but the exact pathway has where the DHp domain of the histidine kinase domain yet to be determined (84). These observations indicate that dimerizes with the DHp of the other monomer (Fig. 2). In this there are likely to be differences in the biochemical output model, the catalytic domain associates with the DHp domain. between receptor isoforms. Although some of these differences The catalytic and receiver domains are modeled to extend out- may arise from different kinase specificities (44, 45), this does ward from the DHp pair. The orientation of the receiver not easily explain all of these differences. domain in relationship to the remainder of the protein is pre- Ethylene receptors are homologous to bacterial two-compo- dicted to be different from prokaryotic histidine kinases, sug- nent receptors. The simplest bacterial two-component system gesting that this domain may be diverged in function from pro- signals by histidine autophosphorylation followed by relay of karyotes (68). Additionally, structural studies show that the the phosphoryl to a conserved aspartate on a receiver domain of -loop of ETR1, which is part of the catalytic region of receiver a response regulator protein, although more complex varia- domains, is in a different orientation from characterized pro- tions of this exist (13). Despite the fact that ETR1 possesses karyote receiver domains (42, 68). No structural information is histidine kinase activity that is modulated by ethylene (44, 45, published characterizing the ethylene-binding domain, but a 88), this activity is not required for responses to ethylene (89, computational model is available (69). This study coupled with 90). Rather, it may subtly modulate receptor signaling to down- prior research (20) suggests that ethylene binds in the middle of stream components (81, 89, 91–93), including interactions with helices 1 and 2 and the signal is transduced via helix 3. The EIN2 (94). Similarly, receptor serine/threonine kinase activity mechanistic details of this transduction through the receptor does not appear to be required for ethylene responses but may are unknown. have a modulatory role in ethylene receptor signal transduction A key issue in ethylene signaling has been to determine how and responses (95). proteins bind ethylene with high affinity, and mutational stud- Complexes of receptor dimers have been proposed to explain ies have identified amino acids in helices 1 and 2 that are impor- the large range of ethylene concentrations that plants respond tant for ethylene binding (20, 21, 41). Based on olefin chemistry, to and to explain how one mutant receptor might affect other, several transition metals were initially suggested as cofactors nonmutant receptors (48, 49, 96–100). As an example, plants for binding activity (70–73). It was later determined that ETR1 can respond to ethylene at levels down to 0.2 nl/liter (101), coordinates copper ions, which act as the cofactor for ethylene which is at least 300-fold below the K of binding to the recep- binding (21). Cys-65 in helix 2 is required for coordination of tors (41). Receptor dimer clusters are proposed as a way for copper because the etr1-1 mutant receptor with a C65Y muta- signal amplification to occur, much like how bacterial chemo- tion is unable to bind copper or ethylene (21, 36, 37, 41). receptors function. In chemoreceptors, ligand binding to one Mutants such as this render the plant ethylene-insensitive. receptor dimer can affect the signaling state of neighboring, Additionally, several studies have determined that the ER unbound receptor dimers to increase signal output (102, 103). membrane–localized copper transporter, responsive to antag- Structural studies suggest that CTR1 or the receptor receiver onist 1 (RAN1), physically interacts with at least some of the domains, or both, may be involved in the formation of ethylene receptors and is needed for delivery of copper and proper bio- receptor clusters (43, 104). It remains to be determined whether genesis of the ethylene receptors (74–78). Because copper co- this is important in ethylene signaling. purifies with the ETR1 dimer with a 1:1 stoichiometry, it was The receptors also form higher-order complexes with other long thought that each receptor dimer contains one copper ion proteins (48). Specific proteins have been identified as interact- (21). Recent experimental evidence, however, indicates that ing partners with all or a subset of the ethylene receptors. This there are two copper ions per receptor dimer that are modeled includes interactions with RAN1 that may be important for 7712 J. Biol. Chem. (2020) 295(22) 7710 –7725 JBC REVIEWS: Ethylene signaling correct delivery of copper to the receptors (78). Other interact- The role of EIN2-N is unknown, but it has diverged from other NRAMP proteins, because no metal transport activity has ing partners are less characterized. Reversion to ethylene sen- been detected in heterologously expressed EIN2 and it cannot sitivity 1 (RTE1) interacts with ETR1 and tetratricopeptide rescue yeast deficient in metal uptake (107, 112). However, repeat protein 1 (TRP1) with ERS1 to modulate signaling (34, there are hints that EIN2-N has a role in ethylene signaling. In 105–107). A homolog of TRP1 in tomato interacts with both rice, mao huzi 3 (mhz3) mutants are ethylene-insensitive, and SlETR1 and never ripe (NR or SlETR3) (108). As will be dis- the MHZ3 protein physically interacts with OsEIN2-N and reg- cussed further below, some of the receptors also interact with ulates OsEIN2 abundance; similar genes have been identified in components of the cytokinin signaling pathway (105, 106, Arabidopsis that affect ethylene signaling (131, 132). These data 109–111). indicate the need to further study EIN2-N to delineate the Two proteins, CTR1 and EIN2, are central components of mechanism by which it affects ethylene signaling. ethylene signaling (112, 113) that physically interact with the By contrast, EIN2-C has two known roles. One is to bind the receptors (33, 94, 114–118) and each other (119). CTR1 is a mRNAs that encode for EBF1 and EBF2, whereupon this pro- serine/threonine protein kinase that functions as a negative tein/RNA complex associates with processing bodies (133, regulator of ethylene signaling (113). EIN2 is required for eth- 134). This results in the degradation of these mRNAs by exori- ylene signaling and is part of the NRAMP (natural resistance- bonuclease 4 (XRN4, also known as EIN5), which is a 5 3 3 associated microphage protein) family of metal transporters; it exoribonuclease known to affect ethylene signaling (133–136). is comprised of a large, N-terminal portion containing multiple A consequence of the degradation of EBF1 and EBF2 mRNA transmembrane domains in the ER membrane and a cytosolic is that degradation of EIN3 and EIL1 and probably EIL2 is C-terminal portion (112). In the case of ETR1, the kinase reduced, leading to more ethylene signaling (126, 128, 129). domain of the receptor is required for interactions with both EIN2-C also contains a nuclear localization sequence (NLS). CTR1 and EIN2, although ETR1 histidine kinase activity is only EIN2-C diffuses into the nucleus, where it associates with EIN2 important for modulating interactions with EIN2 (94, 117, 120). nuclear associated protein 1 (ENAP1), which is required for the These physical interactions appear to be important because ability of EIN2-C to regulate EIN3-dependent transcription mutations in CTR1 that abolish receptor-CTR1 interactions (137). Thus EIN2-C provides both transcriptional and transla- result in a nonfunctional CTR1 (117, 118), and blocking inter- tional control to regulate EIN3 and the related EIL1 transcrip- actions between ETR1 and EIN2 results in ethylene insensitiv- tion factor to cause most ethylene responses. This is supported ity (121). by a recent study where ethylene-stimulated changes in the Current models predict that in the absence of ethylene, the metabolome did not always correlate with changes in the tran- ethylene receptors keep CTR1 active (Fig. 3). CTR1 directly scriptome (138). The exception to this model is that short-term, phosphorylates EIN2 (119), which may result in EIN2 ubiquiti- transient responses occur independently of these transcription nation via an Skp1 Cullen F-box (SCF) E3 ubiquitin ligase com- factors yet require EIN2 (101). Thus, there are more functions plex containing the EIN2-targeting protein 1 (ETP1) and ETP2 for EIN2 that have yet to be discovered. F-box proteins and subsequent proteolysis by the 26S protea- The increase in EIN3, EIL1, and EIL2 activity caused by some (122), as hypothesized in several studies (119, 123–125). EIN2-C leads to changes in the transcription of other ethylene A downstream consequence of this is that the EIN3, EIL1, and response genes, including other transcription factors, such as EIL2 transcription factors are targeted for ubiquitination by an the ERFs (139–141). Recent studies have identified histone SCF E3 complex that contains the EBF1 and EBF2 F-box pro- modifications as having a role in this transcriptional control. teins (126–130). The breakdown of these transcription factors Mutational experiments revealed that several histone acetyl- prevents ethylene responses. Thus, in the absence of ethylene, transferases and histone deacetylases affect ethylene signaling signal transduction in the pathway is blocked because EIN2 (142–144). Additionally, research has identified specific his- levels are low. tone acetylation marks that are important in ethylene-regu- In the presence of ethylene, the receptors are inhibited, lead- lated gene expression by EIN3 (145–147). Even though more ing to less phosphorylation of EIN2 by CTR1. Genetic data pre- details about transcriptional regulation are being discov- dict that the binding of ethylene to the receptors should reduce ered, it is also clear from a recent metabolome study that the catalytic activity of CTR1. However, this has not yet been changes in metabolism occur in response to ethylene that are directly tested. Ethylene enhances the interaction between not predicted by changes in the transcriptome (138). This ETR1 and both CTR1 and EIN2 (66, 94, 117). Thus, an alterna- indicates that there is additional regulation for responses to tive explanation for reduced EIN2 phosphorylation by CTR1 is this hormone. that the binding of ethylene to the receptors results in confor- In summary, the model for the canonical ethylene-signaling mational changes in the receptors that reduces the physical pathway has developed from a simple genetic model to a more interaction between CTR1 and EIN2, leading to less EIN2 phos- complex model with many more biochemical details. However, phorylation. It is thought that when EIN2 phosphorylation is there are still gaps in our understanding of this signal transduc- reduced, there is less EIN2 ubiquitination, resulting in an tion pathway. increase in EIN2 levels and subsequent cleavage of EIN2 by an Noncanonical signaling unknown protease to release the C-terminal portion of EIN2 (EIN2-C) from the membrane-bound N-terminal (EIN2-N) The model discussed above is largely linear, and it summa- portion (119, 122, 124, 125). rizes the main pathway by which ethylene affects plants. None- J. Biol. Chem. (2020) 295(22) 7710 –7725 7713 JBC REVIEWS: Ethylene signaling Figure 3. Model for ethylene signaling. RAN1 is a copper transporter that delivers copper to the lumen of the ER, where it is required for the biogenesis of the receptors and is used as a cofactor by the receptors to bind ethylene. A, in the absence of ethylene, the receptors signal to CTR1, which phosphorylates EIN2. This results in the ubiquitination of EIN2 by an SCF E3 containing the ETP1/2 F-box proteins, leading to EIN2 degradation by the proteasome. Because EIN2 levels are low, an SCF-E3 containing the EBF1/2 F-box proteins ubiquitinates EIN3 and EIL1, leading to their degradation by the proteasome and preventing them from affecting transcription in the nucleus. B, in the presence ethylene, the receptors bind ethylene via a copper cofactor. The binding of ethylene is modeled to cause a conformational change that either reduces CTR1 kinase activity or, as shown, results in CTR1 being sequestered by the receptors so that CTR1 can no longer phosphorylate EIN2. The reduction in EIN2 phosphorylation results in less EIN2 ubiquitination and an increase in EIN2 levels. An unknown protease cleaves EIN2, releasing the C-terminal end (EIN2-C) from the N-terminal end (EIN2-N). One fate of EIN2-C is to bind the RNAs for EBF1 and EBF2 and become sequestered in processing bodies (P-bodies). The reduction of EBF1/2 results in less ubiquitination of EIN3 and EIL1, causing higher EIN3/EIL1 levels. The other fate of EIN2-C is to translocate to the nucleus, where it increases the transcriptional activity of EIN3/EIL1 via ENAP1. This leads to numerous transcriptional changes. In parallel with this pathway, phosphoryl transfer from a conserved histidine in the ETR1 DHp domain to an aspartate in the receiver domain occurs. This is followed by phosphoryl transfer from this residue to AHPs and finally ARRs resulting in transcriptional changes. theless, it is clear from diverse studies that the ethylene-signal- selves can regulate sensitivity, where higher levels lead to less ing pathway involves feed-forward and feedback regulation sensitivity and lower levels to more sensitivity (89, 90, 114, 161– leading to sensitization and adaptation (101, 148–160). Most of 164). However, it is also now clear that other proteins affect this research has identified adaptation mechanisms at the level sensitivity at the levels of the receptors. This includes negative of the receptors. For instance, the levels of the receptors them- regulation by RTE1 and the family of proteins called auxin- 7714 J. Biol. Chem. (2020) 295(22) 7710 –7725 JBC REVIEWS: Ethylene signaling regulated gene involved in organ size (ARGOS) (149, 154, 165, the cytokinin pathway, resulting in changes in transcription 166). An RTE1-like protein, green ripe (GR), has a similar role that modulate ethylene responses (Fig. 3). There is some over- in tomato (166). The exact mechanisms for regulation by these lap between transcriptional changes caused by ethylene and proteins are under investigation. More information about this cytokinin (174), raising the possibility that there are both over- is contained in a recent review (167). lapping and nonoverlapping targets of transcriptional control The existence of nonlinear components to what has been from this signaling pathway involving ETR1 histidine kinase considered the canonical pathway raises the possibility that and the well-known pathway involving EIN3 and EILs. It is other ethylene-signaling pathways exist outside of or as branch interesting to note that in rice, a histidine kinase (MHZ1/ points from this core pathway. This is an area of active research, OsHK1) that may have a role in cytokinin signaling functions and in the cases discussed below, evidence is provided showing downstream of the OsERS2 ethylene receptor and signals inde- that signaling occurs, at least in part, via components not con- pendently of OsEIN2 (175). Thus, our model for canonical eth- tained in the canonical pathway presented above. These alter- ylene signaling probably needs to be expanded to include sec- native (noncanonical) pathways are not necessary for ethylene ondary pathways such as phosphorelay from some of the responses but appear to have roles in modulating responses to ethylene receptors to the AHPs and ARRs. ethylene or in altering responses to other hormones. It should be noted that biochemical experiments show that Results from several studies have led to the suggestion that ETR1 histidine autophosphorylation decreases upon binding of the ethylene receptors signal independently of CTR1 or EIN2 ethylene or ethylene receptor agonists (88, 94), whereas genetic (44, 80, 82–85, 168–170). For instance, epistasis analysis has experiments suggest that ethylene leads to more phosphotrans- shown that the role of ETR1 and ETR2 in the control of seed fer (81, 89). Histidine kinases can carry out multiple enzymatic germination by ABA is, at least in part, independent of CTR1 reactions, including kinase, phosphatase, and phosphotransfer (84). It is possible that such alternative signaling occurs via reactions, and receiver domains can catalyze both phospho- CTR1 homologues, but so far no CTR1 homologue has been transfer and autodephosphorylation reactions (13, 176). Given identified as being involved in this. Even though ETR1 histidine this complexity, one possible resolution to this discrepancy kinase activity is not required for ethylene signaling, this activ- betweenbiochemicalandgeneticdataisthathistidineautophos- ity does modulate sensitivity to ethylene, growth recovery phorylation occurs in the absence of ethylene, but phospho- kinetics when ethylene is removed, growth of root apical mer- transfer to the receiver domain does not occur until ethylene istem, seed germination under stress conditions or in response binds to the receptor to bring the DHp (site of histidine phos- to ABA, and interactions with EIN2 (81, 83, 84, 89–91, 93, 94, phorylation) and receiver domains into the correct orientation. 111). Likely targets for phosphorelay from ETR1 are compo- Thus, ethylene may be increasing phosphotransfer through the nents of the cytokinin signaling pathway (Fig. 1). The cytokinin pathway, causing the steady-state level of ETR1 histidine phos- receptors are two-component receptors in plants that, unlike phorylation to decrease. This will only be answered conclu- the ethylene receptors, use phosphorelay as the primary route sively when we have structural data. for signaling (18, 171). In this pathway, the phosphoryl is trans- Noncanonical signaling is also likely to occur downstream of ferred from the cytokinin receptors to histidine-containing the receptors. For instance, PpCTR1 in Physcomitrella patens phosphotransfer proteins (AHP family in Arabidopsis) and has a role in both ethylene and ABA signal transduction, raising finally to response regulator proteins (ARR family in Arabidop- the possibility that CTR1 has more functions than simply phos- sis) that function as transcription factors. Various studies have phorylating EIN2 (177). Also, mutants of EIN2 have altered demonstrated that ETR1 physically interacts with ARR and responses to various hormones (reviewed in Ref. 178), but AHP proteins (109–111, 172). This interaction involves the whether this reflects alternative signaling from EIN2 or is due to C-terminal portion of ETR1 (109, 111). The affinity between many pathways converging on EIN2 has yet to be completely ETR1 and AHP1 is altered by their phosphorylation state, explored. where it is highest if one protein is phosphorylated and the The signaling pathway downstream of EIN2 is complex other is not (172). because it involves at least two levels of transcriptional regula- In support of interactions between ETR1 and the cytokinin tion. Because of this, it is harder to distinguish “canonical” from pathway having functional consequences, mutational analyses “noncanonical” signaling. EIN3 is the transcription factor with revealed that the ARRs are involved in ethylene responses such the largest role in ethylene signaling (128, 139), and it as sensitivity to ethylene, recovery kinetics after ethylene is homodimerizes to interact with its target DNA (141). However, removed, stomatal aperture control, and the regulation of root environmental factors such as dark versus light or the presence apical meristem (92, 93, 111, 173). Null mutants of ARR1 are of other hormones can affect this so that, depending on condi- less responsive to ethylene, and this appears to depend upon tions, EIN3 interacts with other transcription factors, leading to ETR1 histidine kinase activity (93). Similarly, null mutants in outputs not predicted by the common ethylene-signaling mod- several AHPs and ARRs prolong growth recovery when ethylene els (179–181). As an example, ethylene is well-known for inhib- is removed, similar to what is observed in plants deficient in iting hypocotyl growth in dark-grown eudicot seedlings (36, ETR1 histidine kinase activity (81, 92). Additionally, ETR1 his- 182) and stimulating hypocotyl growth in the light (183–187). tidine kinase activity is involved in both ethylene- and cyto- In the dark, EIN3 directly interacts with another transcription kinin-induced changes in root apical meristem (111). Together, factor, phytochrome-interacting factor 3 (PIF3), forming an these results are consistent with a model where ETR1 histidine output module distinct from either transcription factor alone kinase activity is directly involved in affecting components of (181). A recent meta-analysis of transcriptomic data sets com- J. Biol. Chem. (2020) 295(22) 7710 –7725 7715 JBC REVIEWS: Ethylene signaling paring ethylene-responsive genes in the light versus the dark tomato plants; increased pathogen susceptibility in tobacco; uncovered a set of genes that were similarly regulated in both reduction in seed germination, pollen viability, number of conditions, but also many that were differentially regulated adventitious roots, and root performance in petunias; and (188). It will be interesting to determine which of these differ- reduced femaleness in melon flowers (194, 195, 199–203). entially regulated transcripts are controlled by this EIN3/PIF3 These unwanted effects reduce the efficacy of this approach for module. commercial use. The above summarizes evidence that specific ethylene recep- One potential way around this is to target etr1-1 or another tor isoforms signal to affect other hormone pathways, such as similar receptor mutant that causes ethylene insensitivity to cytokinin and ABA. The exact pathways for this have yet to be tissues of interest. For instance, flower-specific expression of delineated, but it appears that at least some of these roles are etr1-1 reduced flower senescence and increased flower life of independent of CTR1. This also raises the interesting possibil- two plant species (189, 190, 204). A potential problem with this ity that the ethylene receptors are affecting other signaling approach is that ethylene insensitivity can lead to increased pathways via yet to be discovered mechanisms. Additionally, biosynthesis of ethylene (36), which in turn could affect tissues environmental factors can affect the output of this pathway, not expressing the mutant receptor (194). Another way to adding an additional layer of complexity to understanding all of address these issues is to use an inducible promoter for heter- the nuances of how ethylene signaling occurs and how we can ologous expression of the mutant receptor. Relevant to this is manipulate this signaling. the observation that some ethylene receptors are ethylene-in- ducible, including ETR2 from Arabidopsis and NR from tomato Regulating ethylene signal transduction for agricultural (51, 54). Both etr2-1 and nr mutants contain point mutations and horticultural uses that result in ethylene-insensitive plants with long-term ethyl- As can be seen from the information provided above, our ene treatments (40, 54). However, both show a transient understanding about the signaling pathways for the perception response to ethylene and only become insensitive to ethylene of ethylene has grown and become increasingly complicated. when levels of the mutant receptor increase due to increased This increased complexity provides challenges in determining ethylene levels (205). Thus, controlling mutant receptor how to modulate responses to ethylene for commercial pur- expression with inducible heterologous gene expression could poses, but it also provides opportunities to perhaps modulate provide control over both the timing and amount of expression. specific responses without off-target outcomes. This has been used in tomato to delay ripening (206), but it It is likely that signaling pathways comparable with those remains to be determined whether or not this reduces the outlined above in Arabidopsis also occur in most land plant severity of unwanted effects from the transgene. species because similar genes have been uncovered in diverse Another alternative is to find mutants in other genes that plants, including rice, tomato, strawberry, the clubmoss affect ethylene signaling. For instance, down-regulation of Selaginella moellendorffi, and the moss P. patens (4–11). How- SlEIN2 in tomato results in inhibition of ripening (207, 208). ever, it is important to keep in mind that there are also likely to One ethylene-signaling mutant that alters ripening is in the GR be variations on this general signaling pathway that occur from gene in tomato, which has homology to RTE1 in Arabidopsis species to species that need to be taken into account when try- (165, 166). A drawback is that it requires overexpression of GR ing to manipulate ethylene responses. Because ethylene affects to inhibit ripening in tomato (209), leading to issues similar to many processes that are important in horticulture and agricul- those outlined above for heterologous expression of genes. ture, a great deal of research has used the information outlined Fruit ripening, like other developmental processes, is complex above to develop ways to regulate ethylene signal transduction. and is regulated by a network of transcription factors (210). Even though ethylene itself is used for some applications, such Thus, to avoid unwanted effects of mutations, it may be neces- as to cause uniform fruit ripening, most applications involve sary to target specific transcription factors for mutagenesis to minimizing ethylene signaling. These approaches have gener- regulate specific traits affected by ethylene, without altering ally been either genetic or chemical in nature. other responses to this hormone. For instance, virus-induced Early attempts to bioengineer plants that do not respond to gene silencing of SlEIN3 leads to delayed tomato fruit ripening, ethylene involved the heterologous expression of the Arabidop- but no other traits were analyzed to determine whether there sis etr1-1 gene, which, as mentioned above, contains a mutation were detrimental outcomes (211). This will require more that leads to ethylene insensitivity in Arabidopsis. Heterolo- research to link specific transcription factors with specific eth- gous etr1-1 expression leads to ethylene insensitivity and ylene-related traits. reduced flower senescence and longer vase life in several plant Research has also focused on developing chemicals that can species, delayed fruit ripening in tomato and melon, and altered regulate ethylene signal transduction. Silver has long been regeneration in lettuce leaf explants (189–197). It is likely that known to block ethylene responses in plants (73). Silver ions are any ethylene-insensitive receptor transgene will have similar larger than copper ions (212–214) yet support ethylene binding outcomes because Nemesia strumosa flower life was extended to heterologously expressed ETR1 (21, 215). This led to an early when heterologously expressing a cucumber etr1-1 homolog hypothesis that silver ions replace the copper in the ethylene (198). A drawback of constitutive expression of ethylene recep- binding site of the receptors, allowing for ethylene binding but tor mutants that cause ethylene insensitivity is unintended preventing stimulus-response coupling through the receptors effects that can have adverse agricultural and horticultural out- because of steric effects (21, 99, 215, 216). This model may be comes. These adverse outcomes include increased stress in incorrect because silver largely functions via the subfamily I 7716 J. Biol. Chem. (2020) 295(22) 7710 –7725 JBC REVIEWS: Ethylene signaling Investigations using details about ethylene signaling, such as receptor-protein interactions and copper as a cofactor for eth- ylene binding, have also resulted in interesting compounds. One such compound is NOP-1, a synthetic octapeptide that was developed based on details about ETR1-EIN2 interactions (121). This peptide corresponds to the NLS in EIN2-C and dis- rupts the interaction between EIN2 and ETR1 in Arabidopsis as well as interactions between SlETR1 and SlEIN2 in tomato (121, 228). NOP-1 binds to various ethylene receptors, includ- ing ETR1 from Arabidopsis, NR and SlETR4 from tomato, and DcETR1 from carnation (229–231). Importantly, NOP-1 leads to reduced ethylene sensitivity in various plants and has been shown to delay tomato fruit ripening and carnation flower senescence (121, 230). Also important is that it can achieve these effects by surface application to the plants. Because the NLS in EIN2s is conserved across many flowering ornamental Figure 4. Chemicals that affect ethylene responses in plants. Many species (229), it is very likely that NOP-1 and derivatives will be strained alkenes, such as 2,5-norbornadiene, trans-cyclooctene, and 1-meth- effective at blocking ethylene responses in most, if not all, plants ylcyclopropene, have been demonstrated to be effective antagonists of eth- ylene responses that function on the ethylene receptors. Other compounds, used in agriculture and horticulture. such as triplin, are agonists of ethylene responses. Triplin is believed to func- There is also interest in applying ethylene or ethylene tion by altering the delivery of copper ions to the receptors. response agonists to open fields. Even though this may seem counterintuitive because of the adverse agricultural effects this receptors, in particular ETR1 (49, 52, 114). Also, silver func- could have (such as increased senescence and abscission), there tions as a noncompetitive inhibitor, suggesting that it binds to a is strong interest in such compounds as a way to control para- site other than the ethylene-binding site to inhibit the receptor sitic weeds, such as species of Striga. Striga is an obligate para- (52, 73), although it is possible that silver has the characteristics sitic plant that is estimated to cause billions of dollars of crop of a noncompetitive inhibitor yet acts at the ethylene-binding damage annually and can result in 100% crop loss in many parts site (217). Even though silver ions are effective at blocking eth- of sub-Saharan Africa (232, 233). Striga germinates when other ylene responses in plants, the adverse human health and envi- plants germinate nearby, and one of the major cues for this is ronmental effects of silver limit its use. Additionally, silver has ethylene produced by the host plant, although it is unclear off-target effects, such as altering auxin transport (218). whether this is true for all parasitic weeds (234–240). A strategy Because of this, other compounds have been developed. being explored to control this weed is to stimulate seed germi- Strained alkenes such as cyclic olefins can inhibit ethylene bind- nation in the absence of a host in a process termed suicidal ing and action (219), and they have been studied for commercial germination, because the parasite cannot survive without a host use (for examples, see Fig. 4). They have also been used to char- plant (233, 235, 238, 241–244). Ethylene gas was successfully acterize the ethylene-binding site of the receptors. For instance, used for this purpose in the United States in the 1960s, where even though ethylene is a symmetric molecule, the use of dif- soil contaminated with Striga seeds was fumigated with ethyl- ferent enantiomers of trans-cyclooctene, a competitive antag- ene to stimulate germination of the Striga seeds in the absence onist of ethylene receptors, showed that the ethylene-binding of a host needed for survival (235). This has also been shown to site is asymmetric (220). Of these cyclic olefins, 1-methylcyclo- work to varying degrees in Africa (245, 246). Unfortunately, propene (1-MCP) has a high binding affinity to the ethylene fumigating with ethylene is not a good solution in sub-Saharan receptors and has been patented (221–223). Even though it is Africa where this weed is a severe problem, because the farmers gaseous, it has become commercially successful because a solid cannot afford the expensive equipment needed for fumigating formulation was developed where 1-MCP is released when the soil. Therefore, alternative, less expensive, and more easily formulation is dissolved in water. This effectively blocks ethyl- deployed approaches need to be developed. One approach that ene responses and is currently used to prolong the storage life of was developed is the use of ethylene-producing bacteria to a variety of produce (224). Because the active component is a stimulate germination of Striga (247). Alternatively, application gas, its use is generally limited to enclosed spaces, such as for of ethylene-releasing agents or compounds that stimulate eth- post-harvest storage. ylene biosynthesis by Striga seeds have been shown to increase Because gaseous compounds cannot easily be used in open Striga seed germination (239, 248, 249). However, these space applications, such as open fields, research has focused on approaches are either cost-prohibitive or less effective, so low- finding liquid agonists and antagonists of ethylene receptors cost and effective measures still need to be developed to control that can be used in open locations. Using a chemical genetics parasitic weeds. approach, several such compounds have been identified (225– Concluding remarks 227). One of these compounds, triplin (Fig. 4), mimics the effects of ethylene and was used to help identify the protein The details about ethylene signal transduction provided in antioxidant protein 1 (ATX1) as a key transporter of copper to this review illustrate that we now know many important aspects RAN1 (227). of how plants perceive ethylene. This includes a new apprecia- J. Biol. Chem. (2020) 295(22) 7710 –7725 7717 JBC REVIEWS: Ethylene signaling terases, adenylyl cyclases, and FhlA; GR, green ripe; 1-MCP, tion that the ethylene receptors signal via alternative pathways, 1-methylcyclopropene; NLS, nuclear localization sequence; NR, in addition to the canonical pathway that was originally delin- never ripe; NRAMP, natural resistance-associated macrophage eated in genetic screens. Nonetheless, there are clearly gaps in proteins; PIF3, phytochrome-interacting factor 3; RAN1, respon- our understanding of this pathway with unanswered questions. sive to antagonist 1; RTE1, reversion to ethylene sensitivity 1; Despite decades of research on the ethylene receptors, it is SCF, Skp1 Cullen F-box; TRP1, tetratricopeptide repeat protein 1; still not known what conformational changes occur when the XRN4, exoribonuclease 4. receptors bind ethylene and what enzymatic activity or recep- tor-protein interaction is modulated by this binding event. Determining the output of the receptors is complicated by the References fact that the receptor isoforms have both overlapping and non- 1. Bakshi, A., Shemansky, J. M., Chang, C., and Binder, B. M. (2015) History overlapping roles, indicating that output from the receptors is of research on the plant hormone ethylene. J. Plant Growth Regul. 34, not entirely redundant. We also do not know whether we have 809–827 CrossRef 2. 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Journal
Journal of Biological Chemistry – American Society for Biochemistry and Molecular Biology
Published: May 29, 2020
Keywords: Arabidopsis thaliana; bioengineering; hormone receptor; phytohormone; plant hormone; signal transduction; signaling; constitutive triple response 1 (CTR1); ethylene; ethylene-insensitive 2 (EIN2)