Marys Medicine

Making sense of low oxygen sensing

TRPLSC-927; No. of Pages 10 Making sense of low oxygen sensing Julia , Takeshi FukaoDaniel J. GibbsMichael J. , Seung Cho , Francesco ,, Pierdomenico , Laurentius A.C.J. ,and Joost T. van 1 Center for Plant Cell Biology, Department of Botany and Plant Sciences, University of California, Riverside, CA 92521-0124, USA 2 Division of Plant and Crop Sciences, School of Biosciences, University of Nottingham, Loughborough LE12 5RD, UK 3 Max Planck Institute of Molecular Plant Physiology, Am Muehlenberg 1, 14476 Potsdam-Golm, Germany 4 PlantLab, Institute of Life Sciences, Scuola Superiore Sant'Anna, Piazza Martiri della Liberta 33, 56127 Pisa, Italy 5 Plant Ecophysiology, Institute of Environmental Biology, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands 6 Center for Biosystems Genomics, 6708 PB Wageningen, the Netherlands Plant-specific group VII Ethylene Response Factor (ERF) Oxygen deprivation is a frequent component of flooding transcription factors have emerged as pivotal regulators of flooding and low oxygen responses. In rice (Oryza A key feature of flooding events is the change in levels of sativa), these proteins regulate contrasting strategies of ethylene, due to a near 104 flooding survival. Recent studies on Arabidopsis thaliana reduction in their diffusion in water relative to air group VII ERFs show they are stabilized under hypoxia The flooding of root systems – a condition termed but destabilized under oxygen-replete conditions via the waterlogging – has little or no impact in semi-aquatic N-end rule pathway of targeted proteolysis. Oxygen- species such as rice that constitutively form gas conduits dependent sequestration at the plasma membrane (i.e. aerenchyma) between submerged and aerial organs.
maintains at least one of these proteins, RAP2.12, under However, if plants lack gas conduits or lose oxygen from normoxia. Remarkably, SUB1A, the rice group VII ERF roots, waterlogging rapidly reduces the oxygen concentra- that enables prolonged submergence tolerance, appears tion within cells . The presence of aerobic microbes to evade oxygen-regulated N-end rule degradation. We in the soil can further exacerbate the stress. When both the propose that the turnover of group VII ERFs is of eco- root and aerial portions of a plant are whelmed by water – a logical relevance in wetland species and might be ma- condition termed submergence – cellular oxygen levels can nipulated to improve flood tolerance of crops.
also decline from normoxia. The degree of oxygen deficien- cy (hypoxia/anoxia) depends on multiple factors including Improved crop survival of floods is needed replenishment of oxygen through photosynthesis, inward Based on conservative expectations of human population diffusion from the water layer and cellular consumption of growth, the maintenance of international food security oxygen through metabolic activity. Severe oxygen defi- will require a doubling of agricultural productivity in the ciency compromises mitochondrial respiration next two decades . This challenge is exacerbated by and leads to an insufficiency in ATP for energy demanding severe weather events associated with climate change processes However, plants can adjust to this such as floods, which have occurred with increasing fre- energy crisis through increased substrate level ATP pro- quency across the globe over the past six decades duction (This is accomplished by catabolism of (However, improvement of crop resilience to soluble sugars and in some species or cell types starch .
water extremes can be accomplished by harnessing natu- Typically, the increase in glycolytic flux is coupled with ral genetic diversity in breeding programs. An example of regeneration of NAD+ by fermentation of pyruvate to this is the use of the rice SUBMERGENCE 1A (SUB1A) gene, which confers prolonged tolerance to submergence (see The effective SUB1A-1 allele was iso- lated from an eastern Indian landrace and has been Anoxia: absence of oxygen.
returned to farmers in high-yielding varieties This Direct oxygen sensing: sensing of oxygen via its molecular interaction with a ligand (i.e. enzyme, protein, chemical compound) that results in an effect of new ‘Sub1 rice' promises to help stabilize harvests in rain- fed floodplains, which represent 33% of rice acreage world- Hypoxia: oxygen levels below normoxia; the term ‘hypoxic' is often used to wide The task remains to improve flooding tolerance of describe a situation where molecular oxygen is still present, but its level has significantly decreased below 20.6%; cellular oxygen status may be hypoxic or other crops. Recent comparative studies within and be- anoxic dependent upon duration, location and metabolic activity.
tween species have greatly enhanced our understanding of Hypoxia-responsive genes: genes with transcripts differentially regulated in response to conditions with a low oxygen component.
mechanisms that facilitate survival of distinct flooding Indirect oxygen sensing: sensing of change in homeostasis that is a regimes (With new insights into low oxygen consequence of oxygen deprivation (i.e. change in ATP, ADP, AMP, other sensing and response mechanisms we are optimistic that metabolite, Ca2+, ROS, pH) that results in an effect of cellular consequence.
Normoxia: typically 20.6% oxygen at 1 atm and 20 8C.
effective means to lessen crop devastation by flooding can Submergence: waterlogging and partial to complete immersion of aerial be extended beyond rice paddy fields.
Waterlogging: flooding of root system.
Corresponding author: Bailey-Serres, J. 1360-1385/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. Trends in Plant Science xx (2012) 1–10

TRPLSC-927; No. of Pages 10 Trends in Plant Science xxx xxxx, Vol. xxx, No. x events per decade TRENDS in Plant Science Figure 1. Numbers of floods have increased in each of the past six decades across the globe. Graphs show the number of floods classified as a disaster in the International Disaster Database of the University of Louvain, Belgium for the period from 1950 through 2009 by geographical region Events include river or coastal floods, rapid snow melts, heavy rainfall and other occurrences that caused significant social or economic hardship. Adapted from a Millennium Ecosystem Assessment map ( ethanol via pyruvate decarboxylase and alcohol dehydro- synthesis , increased production of heat shock proteins genase (ADH). Because ethanol diffuses out of cells into as molecular chaperones and adoption of the K+-gra- the external milieu, its production depletes the plant's dient to energize membrane transport . Plant survival carbon reserves. Therefore, metabolism of pyruvate to of waterlogging or submergence also depends on their alanine provides an alternative, non-detrimental end ability to limit or endure oxidative stress, which occurs product of anaerobic metabolism that is observed in a during the transition from normoxia to anoxia as well as number of species . This includes the generation upon de-submergence .
of 2-oxoglutarate as a coproduct, which can be further metabolized to succinate, via the TCA cycle enzyme succi- Ethylene initiates submergence survival strategies in nate CoA ligase (SCS), thereby providing additional ATP rice and wetland species per molecule of sucrose metabolized. To keep these reac- Recent work has exposed mechanisms of response to sub- tions running, the oxidation of NADH in the mitochondrial mergence that center on growth management. Notable are matrix is guaranteed by reduction of oxaloacetate via the two antithetical survival strategies displayed by both wild reversed TCA cycle reaction catalyzed by malate dehydro- and domesticated species. For example, deepwater rice, genase The malate produced is probably further cultivated to cope with slowly advancing floods, expends converted to fumarate and succinate , the latter of energy reserves in the elongation of internodal regions that which could be exported from hypoxic tissue to the aerated are underwater to maintain photosynthetic tissue above parts of the plant. At least in tubers of potato (Solanum the air–water interface . Similarly, the wetland tuberosum), hypoxia stimulates a rearrangement of the dicot Rumex palustris, which is well adapted to shallow mitochondrial respiratory supercomplexes that enhances but prolonged floods, reorients and extends petioles to regeneration of NAD+ by the alternative NAD(P)H dehy- elevate leaves above the surface of floodwaters How- drogenases .
ever, this ‘submergence escape' strategy is unsuccessful if Even though the efficiency of hypoxic ATP production is energy reserves are exhausted before escape of the deluge.
low compared to aerobic oxidative phosphorylation, it In wetland species capable of surviving transient floods allows cells to survive as long as carbohydrate substrate (e.g. Rumex acetosa) and submergence tolerant Sub1 remains available. Cell death only becomes inevitable rice , a ‘quiescence strategy' minimizes energy expen- when there is insufficient energy for exclusion of protons ditures for growth until de-submergence.
to the apoplast to prevent membrane depolarization and to The genetic determinants and hormonal signaling path- maintain a near neutral cytosolic pH Avoidance ways that underlie the two flooding survival strategies of the severe energy crisis associated with low oxygen have been identified. In rice, both strategies utilize the stress requires economization of ATP consumption. Means phytohormone ethylene and ethylene response factor to this end include energy efficient sucrose catabolism (ERF) transcription factors. Combined physiological and through sucrose synthase , the preferential use of molecular dissection of submergence responses in rice and PPi-dependent enzymes constrained catabolism of R. palustris has yielded a model in which a buildup of storage compounds such as starch, lipid and protein ethylene in submerged organs initiates a hormonal signal- , metabolic compartmentalization , reduced protein ing cascade that reduces the antagonism between abscisic

TRPLSC-927; No. of Pages 10 Trends in Plant Science xxx xxxx, Vol. xxx, No. x Table 1. Factors that contribute to survival of flooding or oxygen deprivation survival response Rice (Oryza sativa ssp.
Deepwater to non-deepwater SK1, SK2, ethylene, GA, cultivars; SK1 and SK2 internode elongation; Rice (ssp. indica, aus Near isogenic lines; SUB1A-1 Growth restriction; SUB1A-1, ethylene, quiescence strategy Rice (ssp. indica) Anaerobic germination of Enhanced coleoptile and Quantitative trait loci; tolerant to non-tolerant cultivars; cipk15 mutant degradation; CIPK15 Rice (ssp. indica) Seed germination and coleoptile elongation metabolism; reduced oxygen consumption No germination and Limited adjustment of coleoptile elongation metabolism and oxygen Marsh dock (Rumex Ecotypes with fast and slow Petiole elongation Fast elongation associated underwater elongation with lower endogenous To Rumex palustris Limited petiole elongation Maintenance of ABA under submergence Arabidopsis thaliana Varied survivability Meionectes brownii Variation in light Photosynthetic aquatic Reduced need for shoot adventitious roots Sucrose or glucose-fed a-Amylase produced wheat seeds survive under anoxia in rice but not in wheat seedlings Wild type to mutant Transcriptomic and Versatile metabolic metabolic adjustments adjustments such as H To pea (Pisum sativum) Turion elongation and Enhanced H+ extrusion and stabilization of Grape (Vitis sp.) Anoxia tolerant (Vitis riparia) Improved survival of to intolerant (Vitis rupestris) hypoxia pretreated roots maintenance of ion homeostasis (e.g. K+) Arabidopsis thaliana Wild type to loss-of-function Low oxygen and/or HRE1, HRE2, RAP2.2, or other insertion mutants submergence survival and overexpression Wild type to loss-of-function Low oxygen and/or N-end rule pathway prt6 and ate1ate2 mutants submergence survival; components PRT6, ATE1, seed germination under Wild type to loss-of-function Seed germination under NAC transcription factor mutants and overexpression Wild type to N-deficient Alanine and succinate Modified TCA flux mode nodular leghemoglobin RNAi Poplar (Populus  Transcriptomic and metabolic adjustments; limited shoot response Cotton (Gossypium Transcriptomic and metabolic adjustments; shoot growth inhibition Root cell type mRNAs Aerenchyma formation Ethylene, Ca2+, ROS; Response to compounds Adventitious root Epidermal cell death mediated by ethylene and Response to hormone Adventitious root Ethylene and auxin biosynthesis inhibitors

TRPLSC-927; No. of Pages 10 Trends in Plant Science xxx xxxx, Vol. xxx, No. x species to keep pace with increased carbon Sucrose degradation shifts from INV to SUS; some species use PPi consuming enzymes in sucrose breakdown and glycolysis, increasing net Upregulated by low production of ATP oxygen (Pasteur effect) to increase substrate level ATP production Alanine and 2OG shunt
Prevents loss of carbon via fermentation and routes 2OG into the oxidative TCA branch to yield additional ATP by substrate level phosphorylation NH + NADP(H) NAD(P)+ Induced by low oxygen; aids redox equilibration and provides NAD+ to maintain glycolysis downregulation of net GABA shunt
NADH production via the TCA cycle or reduced mETC activity; conserves oxygen may help stabilize TRENDS in Plant Science Figure 2. Metabolic reconfiguration under low oxygen stress. Reduced oxygen availability alters metabolism to maximize substrate level ATP production. The model depicts the major known changes that include enhanced sucrose–starch metabolism, glycolysis, fermentation, a modified tricarboxylic acid (TCA) flow, an alanine and 2- oxoglutarate (2OG) shunt and a g-aminobutyric acid (GABA) shunt. The hypothesis that oxygen is conserved is under further investigation. Yellow boxes summarize notable metabolic adjustments. Blue lines indicate pathways enhanced during the stress, blue dashed lines indicate pathways proposed to be active during the stress and gray dashed lines indicate reactions that are inhibited during the stress. Metabolites that increase during the stress are shown in enlarged black font; metabolites that decrease are shown in red font. Abbreviations are as follows: 2OG, 2-oxoglutarate; ADH, alcohol dehydrogenase; GAD, glutamic acid decarboxylase; GDH, glutamate dehydrogenase, INV, invertase; LDH, lactate dehydrogenase; MDH, malate dehydrogenase; PDC, pyruvate decarboxylase; SCS, succinyl CoA ligase; SUS, sucrose synthase.

TRPLSC-927; No. of Pages 10 Trends in Plant Science xxx xxxx, Vol. xxx, No. x acid (ABA) and gibberellins (GA), which normally limits Similarities in transcriptome response to flooding and cell elongation. In rice, natural variation in the presence oxygen deprivation and absence of the underwater escape [SNORKEL (SK) 1 Numerous investigations have assessed changes in tran- and 2] and submergence tolerance (SUB1A) group VII ERF scriptomes in response to low oxygen stress or flooding in determinants underlies differential regulation of the hor- plants including Arabidopsis, rice, poplar (Populus  monal cascade and hormone sensitivities that control un- canescens) and cotton (Gossypium hirsutum) . Stud- derwater growth (Two R. palustris populations ies performed on seedlings of the Arabidopsis Col-0 eco- distinguished by fast and slow underwater petiole elonga- type include evaluation of the effects of different severity tion were differentiated by the maintenance of higher and duration of oxygen depletion, as well as levels of ABA and reduced GA responsiveness in the slow the impact of heat stress prior to anoxia . Because the elongating variety during submergence . Consistently, majority of cellular mRNAs are poorly translated during the limited underwater petiole growth and prolonged sub- oxygen deprivation changes in polyribosome-associ- mergence survival of R. acetosa was linked to maintenance ated mRNAs were used to evaluate dynamics in the stress of ABA biosynthesis that translated into lower GA respon- and recovery responses . In 21 cell types or regions of siveness during submergence roots and shoots, polyribosomes were captured by immu- Photosynthesis can continue in submerged leaves and is nopurification to identify transcripts regulated by short- aided by the gas film that often clings to their surface term oxygen deprivation . This approach identified 49 . It follows that the degree of oxygen deprivation in core hypoxia-responsive genes that were strongly induced photosynthetic tissue may be less extreme than tissues by the stress across all samples evaluated. Also distin- distant from an oxygen source. Nevertheless, the ethylene- guished were cohorts of mRNAs that were hypoxia-re- driven underwater elongation of shoot tissue can deplete sponsive at the organ or cell-specific level, although carbohydrates and lead to an energy crisis.
their modulation was less pronounced than the core Box 1. Contrasting submergence survival strategies of rice Most accessions respond to submergence through rapid shoot elongation, which allows emergence from a shallow flood A Progressive flood – deepwater rice (SK1/2)
limited number of accessions display the ability to survive a slow progressive flood (escape response) or a deep transient flash flood (quiescence response) (). (a) By amplifying the elongation of stem internodes, deepwater rice can outgrow a progressive flood and survive partial inundation for months. This deepwater escape strategy is controlled by the SNORKEL (SK) locus, which encodes two group VII ERFs, SK1 and SK2 SKs are absent from lowland varieties. (b) The molecular genetic analysis of the submergence-tolerant acces- sion FR13A revealed that the SUBMERGENCE 1 (SUB1) locus, encoding two or three group VII ERFs, regulates the quiescence response. SUB1B and SUB1C are invariably encoded at SUB1 in lowland accessions, whereas SUB1A is limited to some indica and Flash flood – Sub1 rice (SUB1A)
aus landraces The SUB1A-1 allele is sufficient to confer survival of 2 weeks or longer of complete submergence. (c) Model of the core submergence response network that is influenced by SKs and SUB1A.
Genotypes possess either SK1/SK2, SUB1A or neither. Both SK1/SK2 and SUB1A-1 mRNA are ethylene induced. In deepwater rice, SK1/ SK2 and two minor QTLs augment accumulation of bioactive GA in stem internodes during submergence. In submergence tolerant rice varieties, the presence of SUB1A-1 influences submergence and post- submergence responses in aerial tissue. (1) SUB1A-1 mRNA is ethylene-induced but ultimately limits ethylene biosynthesis (2) SUB1A-1 promotes accumulation of two negative regulators of GA responses [SLENDER RICE 1 (SLR1) and SLENDER RICE-LIKE 1 (SLRL1)] . (3) SUB1A-1 does not perturb the submergence- induced decline in ABA content but heightens sensitivity to ABA . (4) SUB1A-1 limits induction of genes associated with starch breakdown . (5) SUB1A-1 enhances upregulation of genes associated with reactive oxygen species (ROS) amelioration and survival of dehydration, thereby improving re-establishment follow- ing de-submergence (6) SUB1A-1 interacts with a complex network of proteins . (7) SUB1A-1 transiently restricts the progression to flowering during submergence In summary, SUB1A is remarkably positioned to suspend growth and maintain cell viability during submergence and restore homeostasis during a subsequent recovery period.
TRENDS in Plant Science Figure I. Group VII ERFs and pathways that regulate growth responses under distinct flooding regimes.

TRPLSC-927; No. of Pages 10 Trends in Plant Science xxx xxxx, Vol. xxx, No. x hypoxia-responsive genes. Of the 49 core hypoxia-respon- Group VII ERFs regulate low-oxygen acclimation sive genes, 24 were also differentially regulated in roots and rosette leaves during submergence in complete dark- The plant-specific ERF transcription factor family includes ness Finally, meta-analyses that compared tran- over 100 members in rice and Arabidopsis, all of which scriptomic adjustments to low oxygen or flooding stress share an APETALA2 (AP2) DNA binding domain . The identified conservation in the core network of genes asso- ERFs have been phylogenetically parsed into ten clades, ciated with signaling, transcription and efficient anaero- with the group VII ERFs characterized by a conserved N bic ATP production that is modulated by oxygen terminal motif (NH deprivation in a range of plants .
rice (japonica cv. Nipponbare) ERFs were designated group VIIa (OsERF59-72) and VIIb (OsERF73), based on How do plant cells sense low oxygen stress? the presence or absence of the conserved N terminal motif, Based on mechanisms in other eukaryotes, both indirect respectively. The single group VIIb ERF corresponds to and direct sensing of cellular oxygen status could be re- SUB1C, which is found in all rice varieties surveyed sponsible for acclimation responses that prolong survival and acts downstream of SUB1A Intriguingly, the of oxygen deprivation in plants Indirect sensing group VII ERFs encoded by SUB1A, SK1 and SK2 possess mechanisms might include perception of altered energy variant N termini relative to the rice group VIIa ERFs.
status through changes in levels of adenylates (ATP, ADP Arabidopsis encodes five group VII ERFs (AtERF71–75), and/or AMP), consumable carbohydrates, pyruvate, cyto- two of which are hypoxia-responsive genes {HYPOXIA solic pH, cytosolic Ca2+ or localized production of reactive oxygen species (ROS) and nitric oxide (NO).
At1g72360) and HRE2 (AtERF71; At2g47520)]}. As ob- Animal and yeast cells sense and adjust energy homeo- served for SUB1A and the SKs, HRE1 mRNA accumula- stasis through Sucrose Non-Fermenting 1 (SNF1)/AMP- tion is promoted by ethylene, which synergistically activated protein kinases The plant energy sensors enhances its elevation during hypoxia (b).
fall within one clade of SNF1 relatives, the SnRK1s, some Several recent reports indicate that Arabidopsis group of which have been implicated in low oxygen responses. For VII ERFs redundantly regulate hypoxia-responsive gene example, Arabidopsis KIN10 and KIN11 are necessary to expression and survival of low oxygen stress. For example, limit energy consumption during hypoxia Whereas in seedling survival of anoxia was more severely compro- rice seeds germinated under oxygen starvation, the deple- mised in hre1hre2 double mutant seedlings than in either tion of sucrose activates the SnRK1A energy sensor single mutant or the wild type . By contrast, low through the activity of a Calcineurin B-like interacting oxygen sensitivity was lessened in seedlings that constitu- binding kinase 15 (CIPK15) . This signal transduction tively overexpress either HRE1 or HRE2 mRNA. The upregulates transcription of genes encoding a-amylases, ectopic expression of these ERFs was sufficient to heighten which drive catabolism of starch in the seed needed to fuel induction of the core hypoxia-responsive gene ADH1 or underwater shoot growth. Logically, a reduction of energy ADH enzyme activity during the stress . However, consumption is beneficial when ATP levels decline. A because hre1hre2 seedlings were able to elevate ADH means of energy conservation during low oxygen stress enzyme activity and ethanol production during hypoxia in plants is selective translation and sequestration of genetic redundancy is likely to extend to the other mRNAs during hypoxia Based on evidence from other group VII ERFs [RAP2.12 (AtERF75; At1g53910), RAP2.2 eukaryotes, the sequestration of a subset of cellular (AtERF74; At3g14230) and RAP2.3 (AtEBP/AtERF72; mRNAs, such as the abundant cohort that encodes ribo- somal proteins and translation factors, could be regulated RAP2.12 was sufficient to elevate expression of a pADH1:- through SnRK1s and the Target of Rapamycin kinase .
LUCIFERASE transgene and RAP2.2 overexpression Mitochondria are also thought to contribute to oxygen improved survival of hypoxia in seedlings whereas the sensing and signaling in plants, through production of inhibition of either RAP2.2 or RAP2.12 expression via NO and/or release of ROS and Ca2+ during the transition miRNA production limited the induction of ADH1 and from normoxia to hypoxia as confirmed in animals several other hypoxia-responsive genes . The impact of ectopic expression of these genes was condition specific, In animals, direct oxygen sensing regulates the accu- as HRE1, HRE2, RAP2.2 and RAP2.12 overexpression mulation of the a subunit of the hypoxia inducible factor significantly increased levels of ADH1 mRNA or ADH (HIF) 1a/b transcription factor HIF1a is constitu- activity under low oxygen stress but not under normoxia tively synthesized but fails to accumulate under nor- Nonetheless, RAP2.2, RAP2.3 and RAP2.12 moxia because of oxygen-dependent hydroxylation of mRNAs accumulate under normoxia in association with specific proline residues that trigger its ubiquitination polyribosomes , suggesting they are constitutively and 26S proteasome-mediated degradation. As oxygen synthesized. Together, these findings hint that post-trans- declines, the prolyl hydroxylases that modify HIF1a lational regulation limits the function of group VII ERFs to are less active. Consequentially, HIF1a accumulates periods of low oxygen stress.
and is trafficked to the nucleus where HIF1a/b can function in transcriptional activation. There is no corol- Arabidopsis group VII ERFs are degraded via the N-end lary direct oxygen sensing mechanism in plants, because although they possess prolyl hydroxylases they lack The conserved N-end rule pathway of targeted proteolysis regulates the half-life of certain cellular proteins based on

TRPLSC-927; No. of Pages 10 Trends in Plant Science xxx xxxx, Vol. xxx, No. x recognition of N terminal residues by specific N-recognin E3 ligases In plants, 11 amino acids function as destabilizing residues when located at the N terminus of a protein, which coupled with an optimally positioned downstream lysine can act as a degradation signal (N- degron) . In plants and animals but not yeast, a cyste- ine (Cys) residue at the N terminus can undergo two steps of modification that lead to protein recognition and degra- dation Based on mechanistic studies in mam- mals, newly synthesized proteins with a Cys as the second are constitutively cleaved by 2–Met1–Cys2) a Met amino peptidase (MAP) to yield NH Arabidopsis group VII ERFs bidopsis, a small family of functionally redundant MAPs catalyzes this reaction . The exposed Cys spontaneously or enzymatically oxidized in an O NO-dependent manner to Cys-sulfinate or further to Cys-sulfonate . As a result of oxidation, an arginine residue is added to the NH Transcription / translation transferase (ATE), targeting the protein for recognition by an N-recognin E3 ligase, leading to ubiquitination and 26S proteasome-mediated degradation. In Arabidopsis, the genes ATE1 and ATE2 encode the Arg transferases and at least one E3 ligase, encoded by PROTEOLYSIS 6 (PRT6), acts as an N-recognin of NH polypeptides .
The distinct conservation of the N terminus of group VII ERFs and the serendipitous observation that an Arabidop- sis prt6 mutant constitutively accumulates ADH1 and other hypoxia-responsive mRNAs in seeds led to the con- firmation that group VII ERFs are bona fide substrates of the N-end rule pathway in plants ( Additional support of this conclusion was obtained through in vitro and in planta analyses.
Anaerobic metabolism An in vitro system derived from rabbit reticulocytes and other responses was used to confirm that all five Arabidopsis group VII ERFs are N-end rule substrates. It was also shown that their instability required Cys as mutation of Cys stabilizing residue Ala 2 (NH2–Met1–Ala2) ceptibility to N-end rule turnover. It was further demon- strated in planta that low oxygen stress increased the accumulation of group VII ERFs synthesized with a native whereas those synthesized 2–Met1–Cys2), terminus were stable under 2–Met1–Ala2 N both normoxia and hypoxia Based on this evidence, the stabilization of group VII ERFs under hypoxia is most probably related to an inhibition of the Cys is required before the protein can be arginylated and TRENDS in Plant Science Figure 3. Oxygen sensing via N-end rule pathway-targeted turnover of group VII Cys by an arginyl tRNA transferase (ATE); and (iv) the argininylated protein is ERFs. (a) N terminal alignment of Arabidopsis group VII ERFs. With the exception recognized by PROTEOLYSIS 6 (PRT6) or other E3 ligases, which polyubiquitinate of SUB1C, all begin with the amino acids ‘Met-Cys' (MC). The highly conserved the protein, targeting it for proteasomal degradation (26S proteasome). The Arabidopsis N terminal motif is boxed in red and is less conserved in the proteins outcome is prevention of transcription of hypoxia-responsive genes under at loci associated with submergence responses in rice. (b) Homeostatic response normoxia. When oxygen becomes limiting (hypoxia), degradation of the ERFs by to hypoxia is regulated by the N-end rule-mediated proteolysis of group VII ERFs in the N-end rule pathway is inhibited due to a lack of oxygen-mediated Cys Arabidopsis. Group VII ERF transcription factors are either constitutively expressed oxidation. Stabilized ERFs can then drive the transcription of genes that enhance and/or differentially transcriptionally regulated in response to variable signals, anaerobic metabolism and other survival responses. Upon return to aerobic ethylene and darkness. Four of the five ERFs (HRE1, HRE2, conditions, the ERFs are once again destabilized, providing a feedback mechanism RAP2.2 and RAP2.12) have been implicated in the regulation of hypoxia-responsive that allows the plant to return to aerobic metabolism. (c) AtRAP2.12 localization genes. Under oxygen-replete conditions (normoxia), ERFs are degraded via the N- dynamics. At least one group VII ERF, RAP2.12, associates with the plasma end rule pathway of proteolysis. This involves the following steps: (i) the N membrane (PM) via interaction with ACBP, limiting its turnover under normoxia.
terminal Met (M) is constitutively cleaved by a methionine aminopeptidase (MAP); During hypoxia RAP2.12 is relocated to the nucleus and activates gene expression.
(ii) the exposed Cys (C) is converted to an oxidized (C*) form (e.g. Cys-sulfonic Upon reoxygenation, RAP2.12 is destabilized, presumably as a consequence of NO or possibly ROS; (iii) an Arg (R) residue is added to the oxidized Cys2 oxidation and N-end rule-mediated degradation.
TRPLSC-927; No. of Pages 10 Trends in Plant Science xxx xxxx, Vol. xxx, No. x Either the modification of the N terminus of a group VII Manipulation of N-end rule regulation of group VII ERFs ERF or disruption of an N-end rule pathway step can affect and other proteins survival of low oxygen stress or submergence in Arabi- The verification that the N-end rule pathway modulates dopsis . For example, stabilization of HRE1 and HRE2 group VII ERF accumulation in the nucleus in an oxygen- by modification of the N terminus to NH dependent manner exposes the first examples of N-end 2–Met1–Ala2 was sufficient to improve seed germination and seedling sur- rule substrates and a homeostatic low oxygen sensor mech- vival under hypoxia . In addition, ate1ate2 and prt6 anism in plants. Based on available gene sequence data, seedlings were less sensitive to hypoxia when grown on group VII ERFs with the conserved N-terminus are broad- sucrose-supplemented medium . The same mutants ly found in vascular plant species We propose that grown to the rosette stage were more sensitive to submer- future improvement of flooding tolerance could be achieved gence in complete darkness This discrepancy in by manipulation of synthesis and turnover of these pro- phenotype might be explained by distinctions in the avail- teins (e.g. by overexpression, regulated expression and/or able carbohydrates in the two survival assays. In the low 2–Met1–Cys2 to oxygen experiments, anaerobic metabolism was fueled by Given the crucial importance of modulation of energy sucrose in the medium, whereas in the submergence reserves during flooding, it is not surprising that variation experiments it was limited to endogenous energy reserves of group VII ERF susceptibility to oxygen-dependent N- of the plant. Therefore, the absence of PRT6 or ATE end rule turnover exists in nature. The rice Nipponbare activity may enhance anaerobic metabolism to prolong genome encodes 15 group VII ERFs with the conserved N survival in sucrose-fed seedlings but may cause a more terminus that is consistent with oxygen-regulated N-end rapid onset of energy deficiency in submerged plants.
rule-targeted proteolysis in Arabidopsis. However, neither These findings are reminiscent of the earlier proposal that SUB1A nor SUB1C are N-end rule substrates based on in a balance between energy consumption and conservation vitro data and the N termini of SK1 and SK2 also is crucial to survival of low oxygen stress and submergence deviate from the consensus associated with N-end rule- mediated turnover. This leads us to propose that the It was also observed that the onset of the transcription escape of SUB1A from N-end rule pathway turnover could of hypoxia-responsive genes occurs concomitantly with allow the ethylene-mediated regulation of SUB1A-1 to relocalization of RAP2.12 to the nucleus under hypoxia trigger the sequence of events that promotes the energy (c) . During normoxia, a GFP-tagged version of management associated with submergence tolerance well RAP2.12 was protected against protein degradation by the before oxygen levels reach a critical nadir.
N-end rule pathway of proteolysis and excluded from the nucleus via interaction with a plasma membrane (PM)- Concluding remarks: direct oxygen sensing via the N- associated Acyl-CoA binding protein (ACBP1 or ACBP2).
end rule regulates transcription RAP2.12 migrated to the nucleus in response to hypoxia Alterations in gene expression associated with increased and disappeared from the nucleus after reoxygenation.
catabolism and substrate level ATP production are a Moreover, transient expression of RAP2.12-GFP in leaves hallmark of reduced oxygen availability and flooding in of ate1ate2 and prt6 mutants resulted in greater GFP plants. Group VII ERFs play a prominent role in this signal intensity in the nucleus under normoxia and follow- process. The identification of an oxygen-dependent pro- ing reoxygenation.
tein turnover mechanism that controls the abundance of In summary, the N-end rule pathway of proteolysis some but not all group VII ERFs raises several pertinent regulates the accumulation of group VII ERFs and conse- questions (). We anticipate that genetic manipula- quentially the accumulation of gene transcripts associated tion of the targets of oxygen-regulated N-end rule pathway with low oxygen responses in Arabidopsis. It is proposed turnover can provide a means to improve survival under a that constitutively synthesized group VII ERFs are either variety of flooding conditions.
degraded or sequestered under normoxia, as confirmed for RAP2.12. As oxygen levels fall their degradation becomes Box 2. Key questions for future experimentation limited, PM sequestration is reversed and the ERF is NO or ROS-dependent Cys transported to the nucleus and becomes active in gene ubiquitination of group VII ERFs be experimentally confirmed? If so, is the oxidation spontaneous or catalyzed? expressed and hypoxia-induced group VII ERFs are desta-  What are the kinetics of oxygen-regulated group VII ERF turnover? bilized. Thus, the N-end rule pathway (i) prevents the Does ERF stabilization occur before oxygen deficiency impairs excessive accumulation of constitutively expressed ERFs cytochrome c oxidase activity?  Does the oxygen level affect the interaction between ACBPs and under normoxia; (ii) allows for stabilization of both consti- RAP2.12? Does docking of RAP2.12 to ACBP impair Cys tutive and induced ERFs during hypoxia; and (iii) facil- tion, modification by ATE, or interaction with an E3 ligase? Are itates rapid reversal of ERF-regulated transcription upon other group VII ERFs similarly sequestered? reoxygenation. Constitutively expressed group VII ERFs  What genes and networks are controlled by individual group VII are proposed to encode oxygen sensors that conditionally  Is the activity or turnover of SUB1A, which apparently escapes activate transcription of hypoxia-responsive genes, includ- oxygen-mediated N-end rule degradation, controlled upon de- ing other group VII ERFs The increased synthesis of N-end rule regulated group VII ERFs by ethylene or  Can manipulation of group VII ERF accumulation and turnover darkness could further prime cells for acclimation to oxy- provide an effective strategy to modulate survival of flooding in gen deprivation.
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