Gibberellins (GAs) are phytohormones that regulate growth and development. DELLA proteins repress GA responses. GA binding to its receptor triggers a series of events that culminate in the destruction of DELLA proteins by the 26S proteasome, which removes the repression of GA signalling. DELLA proteins are transcription co-activators that induce the expression of genes which encode products that inhibit GA responses. In addition to repressing GA responses, DELLA proteins influence the activity of other signalling pathways and serve as a central hub from which other pathways influence GA signalling. In this role, DELLA proteins bind to and inhibit proteins, including transcription factors that act in the signalling pathways of other hormones and light. The binding of these proteins to DELLA proteins also inhibits DELLA activity. GA signalling is subject to homoeostatic regulation through GA-induced repression of GA biosynthesis gene expression, and increased production of the GA receptor and enzymes that catabolize bioactive GAs. This review also discusses the nature of mutant DELLA alleles that are used to produce high-yielding ‘Green Revolution’ cereal varieties, and highlights important gaps in our knowledge of GA signalling.

Introduction

Gibberellins (GAs) are a class of compounds with a tetracyclic diterpenoid structure that are produced in plants, fungi and bacteria. In plants, the majority of these compounds are biosynthetic precursors of the active hormones, namely gibberellin A1 (GA1), gibberellic acid (GA3), gibberellin A4 (GA4) and gibberellin A7 (GA7) (Figure 1A), or catabolites of the active hormones or their precursors. GA biosynthesis has been reviewed recently elsewhere [1]. GAs promote both growth by cell expansion and division, and developmental processes such as seed germination, flowering and pollen maturation. The present chapter will focus on five aspects of GA signalling. The first aspect relates to the repression of GA responses by DELLA proteins, and the destruction of these proteins when GA levels increase. The second aspect is the function of DELLA proteins as transcriptional co-activators that interact with DNA-binding proteins to regulate transcription. These topics lead into a discussion of the molecular defects of the semi-dwarfing DELLA alleles that are used in many ‘Green Revolution’ wheat varieties. The third aspect concerns the interaction of DELLA proteins with a number of other proteins, many of which are transcription factors that act in other signalling pathways, and the fact that through these interactions the activity of both partners is affected. The fourth aspect is the homoeostatic regulation of GA signalling, whereby signalling turns off GA synthesis, increases GA catabolism and induces accumulation of signalling pathway components, resulting in a reduction in the GA response. Finally, the gaps in our knowledge of GA signalling are discussed.

Structure, synthesis and catabolism of bioactive gibberellins

Figure 1.
Structure, synthesis and catabolism of bioactive gibberellins

(A) Structures of bioactive gibberellins. The structure in black is GA4 and the letters indicate GAs, with the double bond and/or hydroxy group shown in red. (B) Simplified GA biosynthesis pathway. GA precursors are converted into active GA by GA20ox and GA3ox, and inactivated by GA2ox. The steps shown in green and red are up-regulated and down-regulated respectively by GA.

Figure 1.
Structure, synthesis and catabolism of bioactive gibberellins

(A) Structures of bioactive gibberellins. The structure in black is GA4 and the letters indicate GAs, with the double bond and/or hydroxy group shown in red. (B) Simplified GA biosynthesis pathway. GA precursors are converted into active GA by GA20ox and GA3ox, and inactivated by GA2ox. The steps shown in green and red are up-regulated and down-regulated respectively by GA.

GA signalling involves the destruction of proteins that repress GA responses

DELLA proteins are master regulators that prevent GA responses by regulating gene expression; this topic has been covered by several recent reviews [24]. GA responses are activated in mutants that lack a functional DELLA protein. The mutants are taller and show alterations in biochemical processes and gene expression when wild-type plants are treated with GA. Treatment of these mutants with GA does not produce an additional response, which suggests that the GA responses are fully activated. In addition, the GA responses of these mutants remain fully activated when GA levels are reduced using mutations or chemicals that block GA synthesis.

DELLA proteins are named after a highly conserved sequence consisting of the amino acids aspartic acid (D), glutamic acid (E), leucine (L), leucine (L) and alanine (A) that was noted to be present in the N-terminus of the first identified proteins of this type (Figure 2). This motif and a second nearby motif, called TVHYNP (again named after the amino acids that most commonly occur in it), are the hallmarks of the DELLA family. We shall refer to these two motifs collectively as the DELLA domain. DELLA proteins are part of a large family of plant transcription regulators, known as the GRAS family, that have diverse functions. The GRAS domain is characterized by a number of conserved motifs that span the C-terminal half of the DELLA protein. The DELLA and GRAS domains both participate in repression of GA responses.

DELLA protein diagram indicating the locations of the DELLA, TVHYNP and GRAS motifs, and the DELLA and GRAS domains

Figure 2.
DELLA protein diagram indicating the locations of the DELLA, TVHYNP and GRAS motifs, and the DELLA and GRAS domains

The red line indicates the proposed protein encoded by semi-dwarfing alleles of wheat.

Figure 2.
DELLA protein diagram indicating the locations of the DELLA, TVHYNP and GRAS motifs, and the DELLA and GRAS domains

The red line indicates the proposed protein encoded by semi-dwarfing alleles of wheat.

GA signalling involves several steps that culminate in the destruction of the DELLA proteins by the 26S proteasome [58] (Figure 3). The process is initiated when GA binds in a pocket located near the C-terminal end of the GA receptor GIBBERELLIN-INSENSITIVE DWARF1 (GID1). GA binding causes a flexible region at the N-terminal end to fold across the GA-binding pocket, which exposes a DELLA domain-binding site [9,10]. Assembly of the DELLA protein into a complex with GA and GID1 causes a conformational change in the GRAS domain that allows an F-box protein called GIBBERELLIN-INSENSITIVE DWARF2 (GID2) in rice and SLEEPY1 (SLY1) in Arabidopsis to bind [11,12]. F-box proteins are a large family of proteins that interact with specific proteins and recruit them to the SCF (Skp–Cullin–F-box) E3 ubiquitin ligase complex. Following its recruitment to the SCF E3 ubiquitin ligase complex by SLY1/GID2, the DELLA protein is polyubiquitinated, which marks it for destruction by the 26S proteasome. Although assembly into the GID1–GA–DELLA complex is sufficient to inhibit DELLA activity [13], the process leads to the destruction of the DELLA protein. It is possible that destruction of the DELLA protein facilitates continued GA signalling by freeing GID1 to interact with additional DELLA proteins.

GA signalling

Figure 3.
GA signalling

(A) DELLA proteins bind to a DNA-binding protein (Y) and activate transcription of genes which encode products that inhibit GA responses. (B) GA binding causes a conformational change in the receptor GID1, allowing it to bind DELLA proteins. The DELLA protein changes conformation during assembly into a complex with GA and GID1. This change allows it to assemble into the SCFSLY/GID2–ubiquitin ligase complex, where it becomes polyubiquitinated and subsequently degraded by the 26S proteasome.

Figure 3.
GA signalling

(A) DELLA proteins bind to a DNA-binding protein (Y) and activate transcription of genes which encode products that inhibit GA responses. (B) GA binding causes a conformational change in the receptor GID1, allowing it to bind DELLA proteins. The DELLA protein changes conformation during assembly into a complex with GA and GID1. This change allows it to assemble into the SCFSLY/GID2–ubiquitin ligase complex, where it becomes polyubiquitinated and subsequently degraded by the 26S proteasome.

DELLA proteins are co-activators of transcription

Although DELLA proteins do not have an identifiable DNA-binding domain, chromatin immunoprecipitation experiments have shown that these proteins are associated with gene promoters [14]. Several experimental approaches have shown that DELLA proteins induce the transcription of genes [14,15]. In addition, the DELLA domain has been shown to be a transcription-activation domain [16]. These results suggest that DELLA proteins are transcriptional co-activators that bind other chromatin proteins to induce the expression of genes which encode products that suppress GA responses (Figure 3A). This hypothesis is supported by a series of experiments using transgenic plants that express modified DELLA proteins [16]. The study found that the addition of a strong transcription-activation domain to the DELLA protein increased its growth repression activity, whereas the addition of a strong transcription-inhibition domain reduced its growth-repression activity. Although the GRAS domain does not activate transcription, it is required for DELLA activity. Recent research has clarified the role of the GRAS domain and identified proteins that facilitate DELLA protein binding to chromatin [17,18]. The GRAS domain binds to a group of DNA-binding proteins called indeterminate domain proteins (IDDs). Chromatin immunoprecipitation experiments have shown that IDD and DELLA proteins bind the same promoters. In addition, both IDD and DELLA proteins are required for activation of a synthetic reporter gene with an IDD-binding site. It will be interesting to determine whether DELLA proteins co-activate transcription exclusively through interactions with IDD proteins, or whether they bind other DNA-binding proteins.

Mutant DELLA proteins underlie the ‘Green Revolution’

One innovation of the ‘Green Revolution’ was the use of semi-dwarfing genes to create higher-yielding cereals. Nitrogen fertilizer increases seed yield but also promotes stem elongation, which weakens the stem and lowers the harvestable yield because it makes the plant more susceptible to lodging (falling over). Semi-dwarf varieties are shorter and have a stronger stem, and are thus less prone to lodging when fertilized. The semi-dwarfing genes that are used in many varieties of wheat are believed to encode a protein that lacks the DELLA domain due to translation being initiated downstream of the DELLA motif [19] (Figure 2). Because the DELLA motif is critical for interaction with GA-bound GID1, the mutant protein is predicted to be less sensitive to destruction in response to GA signalling. In contrast, since the DELLA and TVHYNP motifs can act independently in the activation of transcription [16], the mutant proteins should retain some ability to repress GA responses.

DELLA proteins mediate cross-talk with other signalling pathways

Acting via DELLA proteins, GA influences the activity of other signalling pathways, and vice versa. In addition to binding IDDs, DELLA proteins bind and inhibit the activity of a number of other proteins, including transcription factors, proteins that regulate transcription factors, and co-chaperones (Table 1 and Figure 4). Although these interactions affect many processes, we shall focus specifically on how they regulate growth.

DELLA-mediated cross-talk between the different signalling pathways

Figure 4.
DELLA-mediated cross-talk between the different signalling pathways

In the JA pathway the transcription factors (TFs) are MYC2, GL1, GL3, EIN3 and EGL3.

Figure 4.
DELLA-mediated cross-talk between the different signalling pathways

In the JA pathway the transcription factors (TFs) are MYC2, GL1, GL3, EIN3 and EGL3.

Table 1
Known key DELLA interactors
Gene nameFunctionReference(s)
ALCATRAZ (ALCFruit patterning [35
BOTRYTIS-SUSCEPTIBLE1 INTERACTOR (BOIVegetative growth [38
BRASSINAZOLE-RESISTANT 1 (BZR1) and BRASSINOSTEROID-INSENSITIVE1 EMS-SUPPRESSOR1 (BES1Brassinosteroid signalling [32,33
ETHYLENE-INSENSITIVE 3 (EIN3) and RELATED TO APETALA2.3 (RAP2.3Ethylene signalling [25,39
GA-ASSOCIATED FACTOR1 (GAF1Gibberellin biosynthesis [17
INDETERMINATE DOMAIN1 (IDD1Seed germination [40
INDETERMINATE DOMAIN3 (IDD3Root growth [18
JASMONATE ZIM DOMAIN1 (JAZ1) MYC2 Jasmonic acid signalling [24,26
PREFOLDIN3 (PFD3) PREFOLDIN5 (PFD5Microtubule organization [36
PHYTOCHROME-INTERACTING FACTOR3 (PIF3) and PHYTOCHROME-INTERACTING FACTOR4 (PIF4Light signalling [20,21
PICKLE (PKLChromatin remodelling [41
SCARECROW-LIKE3 (SCL3Seed germination and root growth [42
SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE (SPL9Phase transition [43
SPATULA (SPTSeed germination and vegetative growth [44,45
GLABROUS1 (GL1), GLABROUS3 (GL3) and ENHANCER OF GL3 (EGL3) Trichome development [27
Gene nameFunctionReference(s)
ALCATRAZ (ALCFruit patterning [35
BOTRYTIS-SUSCEPTIBLE1 INTERACTOR (BOIVegetative growth [38
BRASSINAZOLE-RESISTANT 1 (BZR1) and BRASSINOSTEROID-INSENSITIVE1 EMS-SUPPRESSOR1 (BES1Brassinosteroid signalling [32,33
ETHYLENE-INSENSITIVE 3 (EIN3) and RELATED TO APETALA2.3 (RAP2.3Ethylene signalling [25,39
GA-ASSOCIATED FACTOR1 (GAF1Gibberellin biosynthesis [17
INDETERMINATE DOMAIN1 (IDD1Seed germination [40
INDETERMINATE DOMAIN3 (IDD3Root growth [18
JASMONATE ZIM DOMAIN1 (JAZ1) MYC2 Jasmonic acid signalling [24,26
PREFOLDIN3 (PFD3) PREFOLDIN5 (PFD5Microtubule organization [36
PHYTOCHROME-INTERACTING FACTOR3 (PIF3) and PHYTOCHROME-INTERACTING FACTOR4 (PIF4Light signalling [20,21
PICKLE (PKLChromatin remodelling [41
SCARECROW-LIKE3 (SCL3Seed germination and root growth [42
SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE (SPL9Phase transition [43
SPATULA (SPTSeed germination and vegetative growth [44,45
GLABROUS1 (GL1), GLABROUS3 (GL3) and ENHANCER OF GL3 (EGL3) Trichome development [27

DELLA proteins interact with phytochrome-interacting factors 3 and 4 (PIF3 and PIF4) [20,21]. PIF proteins are regulators of light signalling that function as homodimers to induce elongation growth. Light signalling has recently been reviewed [22]. In dark-grown seedlings, PIFs are abundant and promote skotomorphogenesis, the developmental pathway that aids light harvesting by seedlings by directing resources to the promotion of rapid hypocotyl elongation. PIF proteins in turn are inhibited by light. When exposed to light, the photoreceptor phytochrome is converted into its active Pfr conformation and interacts with PIF proteins. This leads to the phosphorylation and degradation of PIF proteins by the 26S proteasome, which turns off skotomorphogenesis, allowing resources to be directed away from elongation growth and into leaf development and harvesting of light energy. Since the amount of phytochrome in the Pfr conformation is determined by both the amount of light and the spectral qualities of light (light that has been reflected from or passed through vegetation is depleted of red wavelengths, which are the wavelengths most effective in conversion of phytochrome to the Pfr conformation), PIFs also regulate the growth of plants in the light. In shaded plants, PIFs induce stem elongation, which helps plants that are adapted to growth in full sunlight to avoid being shaded by competitors. PIFs that are bound to DELLA proteins are unable to function as transcription factors to promote growth. Therefore more PIF becomes available to promote growth after GA-induced DELLA destruction. Conversely, increasing PIF levels reduces the amount of DELLA protein available to inhibit growth.

Jasmonic acid (JA) is a plant growth and defence hormone that is released in response to herbivory and pathogen infection. The mechanisms of JA signalling have been reviewed elsewhere [23]. JASMONATE ZIM DOMAIN (JAZ) proteins repress JA signalling by sequestering and inhibiting the activity of transcription factors. JAZ proteins are degraded by the 26S proteasome in the presence of JA. Upon JAZ degradation, the transcription factors are no longer inhibited, and induce JA responses. Induction of the defence response results in resources being directed away from growth and towards defence. This trade-off between defence and growth is illustrated by the Arabidopsis mutant constitutively express the vegetative storage protein 1 (cev1), which has a constitutive JA response and a smaller rosette diameter, but is more resistant to herbivory and pathogens. Furthermore, the coronatine insensitive1 (coi1) loss-of-function mutant, which is not responsive to JA, is taller than the wild-type but more susceptible to herbivory and pathogens. The antagonistic relationship between plant defence and growth involves DELLA proteins, as they interact with both JAZ and at least five of the JAZ-regulated transcription factors, namely EIN3, MYC2, GLABROUS1 (GL1), GLABROUS3 (GL3) and ENHANCER OF GL3 (EGL3) [2327]. The exact mechanism whereby these interactions function to effectively co-ordinate growth and defence is unclear, as DELLA interactions with JAZ and the JAZ-regulated transcription factors may have opposite effects on JA signalling. For example, when JA induces degradation of JAZ, do the now active DELLA proteins only repress growth, or do some of them inhibit defence responses by binding to JAZ-regulated transcription factors? Freeing DELLA from JAZ is not the only mechanism by which JA inhibits growth, as it also inhibits the growth of mutants that lack DELLA activity.

Ethylene is produced in response to various environmental stresses, and ethylene signalling has been reviewed recently [28]. In etiolated dark-grown seedlings, ethylene causes the ‘triple response’, namely formation of the apical hook, reduced hypocotyl growth and reduced root growth. Ethylene induces the accumulation of ETHYLENE-INSENSITIVE 3 (EIN3), a transcription factor that positively regulates ethylene signalling. In the absence of ethylene, EIN3 is degraded by the 26S proteasome. Ethylene treatment does not induce a triple response in Arabidopsis seedlings that lack EIN3. In contrast, overexpression of EIN3 results in short hypocotyls and exaggerated apical hook curvature even when ethylene is absent. DELLA proteins interact with EIN3 and repress ethylene responses [25]. Earlier studies showed that activation of ethylene signalling also stabilizes DELLA proteins, which repress hypocotyl growth [29]. The mechanism by which ethylene causes DELLA accumulation is unknown, but one possibility is that DELLA is more stable when it is complexed with EIN3. However, it has recently been shown that a small fraction of the DELLA protein becomes covalently modified with the small ubiquitin-like modifier (SUMO) protein when plants are subjected to salt stress [30]. Since SUMO-conjugated DELLA stably binds GID1 and is a potent inhibitor of the destruction of DELLA proteins, its accumulation causes reduced growth. Therefore it is important to determine whether ethylene and other signals stabilize DELLA proteins by this mechanism.

Brassinosteroid (BR) promotes growth, and a review of BR signalling has been published previously [31]. BRASSINAZOLE-RESISTANT 1 (BZR1) and BRASSINOSTEROID-INSENSITIVE 1 EMS-SUPPRESSOR1 (BES1) are positively acting transcription factors in the BR signalling pathway. BZR1/BES1 are degraded by the 26S proteasome in the absence of BR, but are phosphorylated, which stabilizes them and allows them to accumulate in the nucleus, in the presence of BR. Since DELLA proteins interact with them, BR-induced accumulation of BZR1/BES1 both activates BR signalling and reduces growth inhibition by DELLA proteins [32,33]. In addition, BR and GA signalling can have a synergistic relationship, because GA-induced destruction of DELLA will free BZR1/BES1 to promote growth.

GA not only promotes growth, but also affects developmental processes. It accelerates the timing of the transition from the juvenile phase to the reproductive phase. DELLA proteins delay this transition by interacting with SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE (SPL9), a transcription factor that induces the expression of an miRNA that promotes the process [34]. Destruction of DELLA proteins in response to increased GA signalling also frees transcription factors that promote fruit valve margin formation (which is essential for fruit dehiscence and seed dispersal) and the development of leaf hairs (trichomes) [35].

In addition, DELLA proteins can affect cell expansion by interacting with proteins that are not transcription factors. Prefoldin 3 (PFD3) and PFD5 are co-chaperones that function in the cytosol to co-ordinate microtubule organization and polymerization during cell expansion [36]. In elongating cells, microtubules are oriented perpendicular to the axis of expansion. DELLA proteins repress cell expansion by binding and sequestering PFD3 and PFD5 in the nucleus. When sequestered in this location, PFD3 and PFD5 are unable to co-ordinate the correct orientation of microtubules to support elongation growth.

Homoeostatic regulation of GA signalling: GA signalling turns off GA signalling

GA signalling feeds back to turn off signalling. Direct regulation of GA biosynthesis and GA signalling genes is central to this homoeostatic regulation [1]. As GA signalling increases, the expression of genes that encode the terminal steps in the synthesis of bioactive GA and GID1 decreases, and expression of GA catabolic enzymes increases (Figure 1B). The net effect of these changes is to reduce the amount of signalling by increasing the quantity of DELLA proteins. Interestingly, DELLA proteins play a direct role in this process. Transcription of GID1 and the GA biosynthesis genes GA 20-oxidase (GA20ox) and GA 3-oxidase (GA3ox) is directly stimulated by DELLA proteins binding to their promoters through the IDD protein GA-ASSOCIATED FACTOR1 (GAF1) [17]. It is not clear whether DELLA proteins directly repress catabolic gene expression.

Although it might seem counterproductive for signalling to be subject to homoeostatic regulation, turning off signalling is essential for continued signalling. Since GA synthesis occurs in specific locations, feedback regulation potentially affects the shape of the GA concentration gradient as it extends away from cells in which it is being produced

What are the gaps in our knowledge of GA signalling?

The current understanding of GA signalling is rather like viewing a painting with a microscope, in that individual details are readily apparent but it is unclear how they are connected. The challenge for the future is to step back and see the whole picture. Given the complexities of GA signalling and the large number of DELLA-interacting proteins, computational approaches will be required to allow the full picture to emerge. These approaches are beginning to be applied to this problem [37], but more information is needed for them to achieve their full potential. The current list of DELLA-interacting proteins is probably incomplete. Knowledge of the amount of bioactive GAs, DELLA proteins and DELLA-interacting proteins in each cell type is needed. In addition, the binding constants between the different proteins, and the mechanism whereby a change in the abundance of a DELLA interactor affects the amount of DELLA protein available to negatively regulate GA signalling, need to be determined. In addition to being post-translationally modified with SUMO, DELLA proteins can be phosphorylated and possibly modified with O-GlcNAc [2]. Therefore the impact of post-translational modification on DELLA activity must also be determined.

Summary

  • DELLA proteins repress GA responses by stimulating the transcription of genes.

  • GA binding to its receptor triggers destruction of the DELLA protein by the 26S proteasome.

  • DELLA proteins interact with proteins from other signalling pathways. These interactions reduce the activity of the interacting proteins.

  • GA signalling is subject to homoeostatic regulation.

  • Mutant DELLA proteins were used to create the high-yielding semi-dwarf ‘Green Revolution’ cereal varieties.

We thank Kerry Sokol and Kristin Grandt for helpful comments on and discussion of this chapter.

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