Posttranslational modification and trafficking of PIN auxin efflux carriers

MECHANISMS OF DEVELOPMENT

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Posttranslational modification and trafficking of PIN auxin efflux carriers Christian Lo¨fke, Christian Luschnig, Ju¨rgen Kleine-Vehn

*

Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria

A R T I C L E I N F O

A B S T R A C T

Article history:

Cell-to-cell communication is absolutely essential for multicellular organisms. Both ani-

Available online xxxx

mals and plants use chemicals called hormones for intercellular signaling. However, multicellularity of plants and animals has evolved independently, which led to establishment

Keywords: Auxin PIN trafficking Trans Golgi network Phosphorylation Ubiquitylation Degradation

of distinct strategies in order to cope with variations in an ever-changing environment. The phytohormone auxin is crucial to plant development and patterning. PIN auxin efflux carrier-driven polar auxin transport regulates plant development as it controls asymmetric auxin distribution (auxin gradients), which in turn modulates a wide range of developmental processes. Internal and external cues trigger a number of posttranslational PIN auxin carrier modifications that were demonstrated to decisively influence variations in adaptive growth responses. In this review, we highlight recent advances in the analysis of posttranslational modification of PIN auxin efflux carriers, such as phosphorylation and ubiquitylation, and discuss their eminent role in directional vesicle trafficking, PIN protein de-/stabilization and auxin transport activity. We conclude with updated models, in which we attempt to integrate the mechanistic relevance of posttranslational modifications of PIN auxin carriers for the dynamic nature of plant development. Ó 2012 Elsevier Ireland Ltd. All rights reserved.

1.

Introduction

Charles Darwin revealed in his book ‘‘The Power of Movement in Plants’’ a mysterious growth substance that was later termed auxin (after the greek word ‘‘auxein’’, meaning ‘‘to grow’’) (Arteca, 1996; Darwin, 1880; Davies, 1995; Raven, 1992). Auxin belongs to the class of so-called plant hormones that jointly coordinate plant growth. Auxin is essential throughout the plant life cycle and is an important developmental trigger for a plethora of developmental events, such as embryogenesis, postembryonic organ formation and tropistic growth (reviewed in Leyser, 2011). The most abundant and developmentally important auxin is indole-3acetic acid (IAA) and on a cellular level, this phytohormone controls cell expansion, division, and differentiation in a

concentration-dependent manner (reviewed in PerrotRechenmann, 2010). Auxin perception occurs via a multiple receptor mechanism that involves TRANSPORT INHIBITOR RESISTANT1/AUXIN SIGNALING F-BOX (TIR1/AFBs), S-PHASE KINASE-ASSOCIATED PROTEIN 2a (SKP2a) and AUXIN BINDING PROTEIN 1 (ABP1) (reviewed in Sauer and Kleine-Vehn, 2011). While the auxin receptor interplay remains to be unraveled, it appears that auxin-dependent transcriptional reprogramming requires the nuclear F-Box proteins TIR1/ AFBs. Auxin binding to TIR1/AFBs and its coreceptors AUXIN/INDOLE ACETIC ACID (Aux/IAA) will lead to proteasome-dependent degradation of Aux/IAA and the subsequent release of AUXIN RESPONSE FACTOR (ARF) transcription factors (reviewed in Chapman and Estelle, 2009; Leyser, 2006).

* Corresponding author: Address: Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Science Vienna (BOKU), 1190 Vienna, Austria. Tel.: +43 1 47654 6719; fax: +43 1 47654 6392. E-mail address: [email protected] (J. Kleine-Vehn). 0925-4773/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mod.2012.02.003

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SKP2a is another F-Box protein that displays auxin binding capacity and might realize the auxin effect on the cell cycle (Jurado et al., 2010). ABP1 activity differs from that of F-Box proteins as it is seemingly required for regulation of rapid, non-genomic auxin effects at the vicinity of the plasma membrane, but also affects nuclear signaling (reviewed in Perrot-Rechenmann, 2010; Sauer and Kleine-Vehn, 2011). Pathways for auxin biosynthesis are still not fully resolved, and involve tryptophan (Trp)-dependent and -independent routes (reviewed in Ruiz Rosquete et al., 2011). Various redundant pathways have been suggested, but Trp-dependent auxin production via TRYPTOPHAN AMINOTRANSFERASE ARABIDOPSIS 1 (TAA1) and YUCCA appears to represent a main biosynthetic route in Arabidopsis and maize (Mashiguchi et al., 2011; Stepanova et al., 2011; Won et al., 2011). Ester or amide conjugation of auxin provides for largely reversible inactivation of IAA, while auxin oxidation designates auxin for degradation (reviewed in Woodward and Bartel, 2005). However, the cellular abundance of active auxin depends not only on auxin metabolism (biosynthesis, conjugation and oxidation), but also on auxin carriers (Grunewald and Friml, 2010; Scarpella et al., 2010; Sundberg and Østergaard, 2009; Zazimalova et al., 2010; Zhao, 2010). Polar auxin transport has outstanding importance for plant development and contributes to various developmental aspects, such as embryonic axis formation, postembryonic organ formation, tropistic growth responses, vascular tissue development, tissue regeneration, phyllotaxis, apical dominance, or flower and fruit development (Benkova` et al., 2003; Friml et al., 2003; Kleine-Vehn et al., 2010; Prusinkiewicz et al., 2009; Sauer et al., 2006; Scarpella et al., 2006; Smith and Bayer, 2009; Sorefan et al., 2009). Various auxin transporters regulate cellular auxin levels. Most prominent auxin carriers include the AUXIN RESISTENT1/LIKE AUX1 (AUX/LAX) auxin influx carriers, the ATP-BINDING-CASSETTE B (ABCB) and PIN-FORMED (PIN) auxin efflux carriers. The polar plasma membrane localization of PIN auxin efflux carriers determines the directionality of intercellular (polar) auxin transport and has been suggested to impose auxin gradients within tissues (reviewed in Wabnik et al., 2011). The delivery of auxin carriers, such as PIN proteins, to designated target sites requires defined vesicle trafficking routes. Cellular mechanisms that guide vesicle transport determine the destination (subcellular localization), activity and abundance of auxin carriers, which is of key importance for auxin biology. Here we review auxin carrier trafficking and its contribution to plant development. Most of our current knowledge on directional vesicle trafficking is based on the PIN-FORMED (PIN) auxin efflux carriers. Hence, we particularly emphasize on posttranslational modification of PIN proteins and its effects on cellular distribution and activity.

2. Polar auxin transport and the long-standing chemiosmotic hypothesis The so-called chemiosmotic hypothesis for polar auxin transport (Rubery and Sheldrake, 1974) remains up to date remarkably in vogue. IAA is partly protonated at the rather acidic pH of the apoplast and can diffuse through the plasma

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membrane. The cytosolic pH causes IAA deprotonation, resulting in anionic and membrane impermeable molecules. Thus, IAA requires plasma membrane localized transporters to exit the cells. This carrier-driven mechanism enables plant cells to control the directionality and rate of cellular auxin efflux, acting as an important determinant of the spatiotemporal auxin distribution within tissues (reviewed in Tanaka et al., 2006) (Fig. 1). Some auxin carrier families have been identified to date (reviewed in Zazimalova et al., 2010). As before mentioned the most prominent are the AUX1/LAX influx carriers, a subfamily of ABC transporters and the PIN auxin efflux carriers (Bennett et al., 1996; Geisler et al., 2005; Luschnig et al., 1998). Pharmacological and genetic experiments revealed the regulatory importance of auxin carriers for plant development (reviewed in Tanaka et al., 2006).

3.

PIN auxin efflux carriers

The PIN protein family consists of eight members in Arabidopsis thaliana, most of which have been demonstrated to transport auxin either in plant or in heterologous systems (Mravec et al., 2009; Petra´sˇek et al., 2006; Yang and Murphy, 2009). PIN proteins contain a central hydrophilic loop, which separates two hydrophobic regions (each with 4-5 predicted transmembrane domains). According to the length of the hydrophilic loop, the PIN proteins can be divided into two sub-classes: type 1 (PIN1, PIN2, PIN3, PIN4 and PIN7) with a long hydrophilic region and atypical type 2 (PIN5, PIN6 and PIN8) with a shorter hydrophilic region (Mravec et al., 2009). The cellular localization of PIN proteins seems to be predetermined by their respective hydrophilic regions. Type 1 proteins are associated with the plasma membrane, whereas type 2 proteins, such as PIN5, are found at the endoplasmic reticulum (ER). PIN5 regulates intracellular auxin compartmentalization by transporting auxin from the cytosol into the ER lumen. Auxin flux at the ER seems to control the availability of free/active auxin for various subcellular and cellular processes (Mravec et al., 2009). Canonical PIN1-type auxin efflux carriers on the other hand, exhibit polar plasma membrane localization and determine the direction of auxin flow (Wisniewska et al., 2006). PIN polarization at the plasma membrane depends on the cell type and intrinsic PIN-specific cues. For instance, PIN2 shows apical (upper cell side/shootwards) localization in the lateral root cap and in the epidermal cells, while basal (lower cell side/rootwards) in the cortex cells of the root (Mu¨ller et al., 1998). In contrast, PIN1 displays basal polarization in both root stele and -when ectopically expressed- in epidermal cells (Wisniewska et al., 2006). Importantly, developmental and environmental signals are realized by dynamic adjustments in directional vesicle trafficking of the PIN auxin efflux carriers. As such, PIN proteins seem crucial for the flexible nature of plant development (Kleine-Vehn and Friml, 2008). For example, a developmental trigger polarizes PIN1 to the basal cell side in embryonic provascular cells, which then presumably defines the auxin-dependent embryonic root pole specification (Friml et al., 2003). PIN3 and PIN7 localization is non-polar in gravity sensing root columella cells, but

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Fig. 1 – Schematic representation of the chemiosmotic hypothesis of polar auxin transport. Protonated auxin (IAA-H) can passively diffuse into the cell. Nonprotonated auxin (IAA ) is taken up by the proton symporter AUX1/LAX transporters. Cytosolic pH favors the deprotonated form of auxin, which requires transport activity to exit the cell. The polarly distributed PIN1-type proteins mediate the directional export into the apoplast and hence determine the direction of intercellular polar auxin transport. Non-polar distributed ATP-dependent ABCBs facilitate nondirectional auxin efflux. ABCB4 can switch transport direction upon changes in auxin levels. ABCB19 and PIN1 interaction at the plasma membrane increases the substrates specificity to auxin (reduced affinity to BA). NRT1.1 mediates auxin influx at low NO3 conditions. PIN5 auxin carrier mediates the auxin import into the lumen of the ER, where auxin might undergo degradation, conjugation and/or storage. Auxin exporters in the ER are still unknown. AUX1/LAX, AUXIN RESISTENT1/LIKE AUX1; BA, benzoic acid; IAA, indole-3-acetic acid; NRT1.1, NITRATE TRANSPORTER 1.1; ER, endoplasmic reticulum; PIN, PIN-FORMED; ABCB, ATPBINDING-CASSETTE B.

rapidly polarizes in response to gravity stimulation. PIN3 and PIN7 polarization towards the gravity vector presumably initiates asymmetric auxin redistribution, which, subsequently, triggers differential growth responses and ultimately root bending towards gravity (Friml et al., 2002; Kleine-Vehn et al., 2010). In summary, mechanisms of PIN polarity establishment and maintenance are important features of embryonic and postembryonic plant development. Additionally, PIN repolarization and redistribution of auxin flux are highly dynamic, which is tightly connected to intrinsic and extrinsic cues.

4.

Additional auxin transporters

PIN proteins are important regulators for directional, cellto-cell auxin transport. However additional auxin transport-

ers are required to maintain polar auxin transport during plant development. The ABCB subgroup of the ABC transporter superfamily represents plasma membrane-localized auxin transporters (Cho et al., 2007; Geisler et al., 2005; Petra´sˇek et al., 2006). The most extensively studied members are ABCB1/PGP1, ABCB4/PGP4 and ABCB19/PGP19. These transporters export auxin in planta or upon heterologous expression in mammalian cells (Cho et al., 2007; Geisler et al., 2005; Petra´sˇek et al., 2006). Remarkably, ABCB4 has a rather complex transport activity. ABCB4 mediates auxin influx activity, when expressed in Schizosaccharomyces pombe, but under conditions of increased auxin concentrations the transport direction reverses to efflux (Yang and Murphy, 2009), indicating a concentration-dependent modulation in the directionality of auxin flow.

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Unlike PINs, ABCBs display mainly non-polar localization at the plasma membrane (Mravec et al., 2008) but ABCBs and PIN proteins co-localize and interact in microdomains at the plasma membrane, which seemingly increases the substrate specificity for auxin (Blakeslee et al., 2007; Titapiwatanakun et al., 2009). Furthermore ABC transporters might also contribute to plant development by diversified substrate specificity, as exemplified by indole-3-butyric acid (IBA)-efflux mediated by ABCG37 and ABCG36 (Ru˚zˇicˇka et al., 2010; Strader and Bartel, 2009). Regarding the chemisomotic hypothesis, the regulation of auxin influx has a previously unforeseen developmental importance, because, at least in some tissues, passive auxin diffusion seems not to meet the demand of cellular auxin uptake. AUX1/LAX-type plasma membrane proteins are involved in auxin uptake into the cell (Yang et al., 2006). Depending on the cell-type, AUX1 localizes either symmetrically or asymmetrically at the plasma membrane (Swarup et al., 2001). Originally AUX1 was identified in a screen for auxin resistant mutants and loss-of-function mutants show agravitropic root growth (Bennett et al., 1996). Strikingly, the agravitropic root phenotype of aux1 alleles could be rescued by exogenous application of membrane permeable auxin analogue 1-Naphthaleneacetic Acid (1-NAA), supporting a role in auxin uptake (Marchant et al., 1999). In accordance with these assumptions, the H+/IAA symporter AUX1 was demonstrated to facilitate auxin influx in planta and in heterologous systems (Yang and Murphy, 2009; Yang et al., 2006). Apart from AUX1/LAX proteins, NITRATE TRANSPORTER 1.1 (NRT1.1) facilitates cellular auxin uptake, specifically under conditions of limited nitrate availability, providing a link between nutrition sensing and auxin-dependent growth adaptation (Krouk et al., 2010). Overall, our current knowledge on auxin transport mechanisms in higher plants demonstrates the evolution of a range of functionally diversified auxin uptake and efflux activities. Strikingly, some of these carriers appear to exhibit mutual interactions, highlighting the necessity of an extensive repertoire of regulatory switches, in order to maintain auxin homeostasis under a wide range of growth conditions.

5.

PIN protein secretion

PIN gene expression is dynamically controlled and has outstanding importance for plant development (Benkova` et al., 2003; Dello Ioio et al., 2008). Nevertheless, little is known about cellular mechanisms that regulate de novo PIN protein synthesis and secretion. PIN proteins are integral membrane proteins that are synthesized at the ER and either get retained (as in case of type-2 PIN proteins) or transported to the Golgi apparatus, which in case of PIN1 requires a functional tyrosine-sorting motif (Mravec et al., 2009). GNOM-LIKE1 (GNL1) regulates vesicle trafficking between the ER and Golgi (Richter et al., 2009; Teh and Moore, 2007), but might not be of primary importance for PIN secretion, because gnl1 mutants exhibit a decrease in ABCB19 abundance, but do not affect PIN1 and PIN2 (Titapiwatanakun and Murphy, 2009) (Fig. 2).

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PIN1-type proteins further transit through the Golgi (Boutte´ et al., 2006), but nothing is known about PIN protein maturation in the Golgi apparatus. The trans Golgi network (TGN) is a central sorting hub for proteins either to the plasma membrane or to the vacuole (Viotti et al., 2010). Notably, secretion of de novo synthesized PIN1 from the TGN to the plasma membrane has been suggested to be non-polar (Dhonukshe et al., 2008), indicating that establishment of PIN polarity requires endocytosis and subsequent polar recycling (Dhonukshe et al., 2008).

6. PIN recycling between the membrane and the trans Golgi network

plasma

Mechanistically, PIN protein abundance at the plasma membrane can be controlled either via endocytosis or exocytosis. Clathrin plays a major role in the formation of coated vesicles. Genetic or pharmacological interference with clathrin function reduces PIN protein internalization from the plasma membrane (Dhonukshe et al., 2007; Kitakura et al., 2011). Moreover, site-directed mutagenesis of a tyrosine motif in the PIN2 sequence, which is presumably required to interact with a clathrin adaptor complex, affects PIN2 protein internalization (Kleine-Vehn et al., 2011). Intriguingly, the auxin receptor ABP1 promotes clathrin activity (Robert et al., 2010), and it now appears that auxin transiently inhibits clathrin-dependent endocytosis by binding to ABP1 and, thus, promotes its own efflux (Paciorek et al., 2005; Robert et al., 2010). PIN cycling from the endosome to the plasma membrane is controlled by ADP-ribosylation factors (ARF). They mediate vesicle trafficking and are localized on the surface of vesicle membranes, where they interact with their activators, such as the guanine nucleotide exchange factors (GEFs) (Donaldson and Jackson, 2000; Geldner et al., 2003). Additional work demonstrated that ARF-GEFs and ARF-GTPase-activating protein (GAPs), such as GNOM and VASCULAR NETWORK DEFECTIVE 3 (VAN3), are required for endocytosis of plasma membrane proteins, including PINs (Naramoto et al., 2010; Teh and Moore, 2007). However, it remains to be determined how the ARF machinery relates to clathrin- or ABP1-dependent pathways. Internalized vesicles (containing PIN proteins) fuse with early endosomes (EE). In plants EE are functionally defined by the TGN, which serves as a major sorting hub for the secretory and endocytic pathways (Dettmer et al., 2006; Lam et al., 2007). PIN proteins co-localize with the endocytic tracer FM464 in early endosomes (Dhonukshe et al., 2007; Jelinkova et al., 2010) and require the ARF-GEF BEN1/MIN7/BIG5 for early endosomal trafficking (Tanaka et al., 2009). PIN recycling was unequivocally demonstrated by analysing a green-to-red photo convertible EosFP fluorescent reporter upon brefeldin A (BFA) treatment (Dhonukshe et al., 2007). Treatment with BFA reduces PIN protein labeling at the plasma membrane and induces PIN protein accumulation in socalled BFA compartments (Geldner et al., 2001; Steinmann et al., 1999), which mainly consist of cytosolic TGN/EE agglomerations surrounded by the Golgi apparatus (Geldner et al., 2003). After pre-treatment with BFA, to inhibit recycling to the plasma membrane, the PIN2-EosFP could be tracked

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MECHANISMS OF DEVELOPMENT

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Fig. 2 – Schematic depiction of intracellular auxin carrier trafficking. The TGN/EE appears to be the main sorting hub for intracellular trafficking. We assume that TGN/EE subcompartments might be functionally diversified (depicted by different colors). TyrA23 interferes with clathrin adaptor protein-dependent cargo recruitment and inhibits PIN internalization. The recycling of PIN1 to the basal cell side is GNOM-dependent, while the PIN1 trafficking from the TGN/EE to the PVC/MVB is partially BFA sensitive, but GNOM independent. The presumptive phosphatidyl-3-kinase inhibitor WM affects PVC/MVB integrity and reduces PIN targeting to the vacuole. Trafficking of PIN1-type, AUX1 and ABCB1, but not ABCB19 proteins, are BFA sensitive, however, the underlying trafficking mechanisms are distinct. Interaction of ABCB19 and PIN proteins leads to stabilization of PIN proteins at the plasma membrane. ABCB, ATP-BINDING-CASSETTE B; AUX1/LAX, AUXIN RESISTENT1/ LIKE AUX1; BEN1, BFA-VISUALIZED ENDOCYTIC TRAFFICKING DEFECTIVE 1, BFA, brefeldin A; ConA, concanamycin A; ER, endoplasmic reticulum; ES1, endosidin 1; ESCRT, ENDOSOMAL SORTING COMPLEX REQUIRED FOR TRANSPORT; GLN1, GNOMLIKE1; MVB, multivesicular bodies; PIN, PIN-FORMED; PVC, pre-vacuolar compartment; SNX1, SORTING NEXIN-1; TGN/EE, trans Golgi network/early endosome; TyrA23, tyrphostin A23; VSR, VACUOLAR SORTING RECEPTORS; WM, wortmannin.

from the plasma membrane to the endosomes. Furthermore, upon photoconversion of PIN2-EosFP in BFA bodies, the PIN2 protein could be followed back to the plasma membrane after BFA removal (Dhonukshe et al., 2007). These findings strongly support the idea of constant cycles of endocytosis and exocytosis for PIN proteins. PIN protein recycling is not only energetically favorable, but also allows the rapid and dynamic regulation of protein abundance and activity at the plasma membrane. A molecular target of BFA is the ARF-GEF GNOM that is functionally associated with cycling endosomes (Geldner et al., 2003); however, the subcellular localization of GNOM and dynamics therein remains to be defined in further detail. GNOM regulates PIN recycling to the basal side of cells, while apical targeting is GNOM-independent (Kleine-Vehn et al., 2008). Alternative recruitment to the distinct basal and apical targeting pathway eventually enables flexible PIN polarity alterations (Kleine-Vehn et al., 2008). Such a transcytosis-like mechanism appears to be relevant for GNOMdependent polarization of PIN3 upon gravistimulation

(Kleine-Vehn et al., 2010). Similarly, polarity establishment after cytokinesis requires sterol-dependent retrieval of PIN2 from the plasma membrane (Men et al., 2008) and could subsequently involve basal-to-apical transcytosis (Kleine-Vehn et al., 2008). It now appears that PIN polarity maintenance is highly complex and requires the interweaved interplay of localized clathrin-dependent PIN internalization (adjacent to the polar domain) and highly defined recycling to the inner core of the polar domain (Kleine-Vehn et al., 2011). Moreover, PIN protein mobility within the plasma membrane is reduced due to defined membrane clusters and interaction with the cell wall (Feraru et al., 2011; Kleine-Vehn et al., 2011), adding additional layers of regulatory complexity to the control of PIN polarity.

7.

PIN phosphorylation guides polar recycling

Reversible phosphorylation is an important regulatory mechanism to control enzyme activity or distribution. Kinases (phosphotransferases) reversibly transfer a phosphate

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from a high-energy donor molecule to a specific substrate. In contrast, phosphatases reverse the kinase activity by hydrolysing the phosphate group. Such a binary switch-like mechanism often regulates protein activity or recognition. In mammalian epithelial cells, for example phosphorylation of the immunoglobulin receptor initiates its transcytosis to the apical cell membrane (Casanova et al., 1990). In plants, early experiments demonstrated that pharmacological interference with kinase and phosphatase activity affects polar auxin transport, linking protein phosphorylation to components of the auxin transport machinery (Delbarre et al., 1998; Garbers et al., 1996; Rashotte et al., 2001). The Ser/Thr protein kinase PINOID (PID) phosphorylates the hydrophilic loop region of PIN proteins whilst the PROTEIN PHOSPHATASE 2A (PP2A) antagonizes PID activity (Michniewicz et al., 2007). Both, overexpression of PID (Friml et al., 2004) and reduced PP2A function (Michniewicz et al., 2007) lead to increased PIN phosphorylation and consequently to a basal-to-apical shift in PIN1 localization (Friml et al., 2004; Michniewicz et al., 2007) (Fig. 3A). Several PID-dependent phosphorylation sites have been identified in PIN proteins. The evolutionary conserved TPRXS (S/N) motif found in the cytosolic loop of type 1 PIN proteins is phosphorylated at its central serine residues by PID (Huang et al., 2010). Site directed mutagenesis of these serine (Ser231, Ser252 and Ser290) residues (to alanine) abolishes the PIN phosphorylation at these residues and leads to preferentially basal PIN targeting. In contrast, phosphomimetic substitutions at these sites, mimicking constitutive phosphorylation, induce apical PIN1 localization (Huang et al., 2010). Additional phosphorylation sites (Ser337 and Thr340) in the hydrophilic loop of PIN1 were identified and shown to be functionally important for polar PIN distribution and auxin transport (Zhang et al., 2010). PID does not directly phosphorylate Ser337 and Thr340 in vitro, suggesting that other kinases may be also involved in the regulation of PIN polarity (Zhang et al., 2010). In agreement with this assumption, the complete loss of TPRXS (S/N) phosphorylation sites also influences cellular processes, which are not necessarily related to PID action (Huang et al., 2010). PID belongs to the large cAMPdependent protein kinase A/cGMP-dependent protein kinase G/protein kinase C (AGC) family. Another AGC kinase, D6 PROTEIN KINASE (D6PK) was demonstrated to phosphorylate PIN proteins. Interestingly, the D6PK kinase had no effect on PIN polarity and might rather regulate the rate of polar auxin transport (Zourelidou et al., 2009). Collectively, experimental work demonstrated that the polar distribution of PIN proteins depends on the PIN phosphorylation at defined residues (Huang et al., 2010; Kleine-Vehn et al., 2009; Zhang et al., 2010). Moreover, it now appears that hypo- or non-phosphorylated PIN proteins enter the basal, GNOM-dependent recycling pathway, whereas highly phosphorylated PIN proteins show GNOM independent, apical targeting (Kleine-Vehn et al., 2009) (Fig. 3A). Nevertheless, sites or cellular compartments where PIN phosphorylation and/or dephosphorylation takes place are still not known. Notably, PID co-localizes with PINs at the plasma membrane (Dhonukshe et al., 2010; Kleine-Vehn et al., 2009; Michniewicz et al., 2007) and, hence, might phosphorylate PIN proteins at this domain. Subsequent internalization and endosomal resorting

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of phosphorylated PIN proteins might then transmit PIDmediated effects on PIN polarity.

8.

Vacuolar sorting at the trans Golgi network

Next to transcriptional or translational control of gene expression, adjustments in protein sorting and proteolytic turnover allow for quick responses to modulate PIN levels and localization. Specifically, PIN recycling and transcytosis were suggested to allow for rapid adjustments in direction and rates of auxin flow, crucial for the orchestration of cell proliferation and adaptive growth responses in a developmental context (Dhonukshe, 2009; Dhonukshe et al., 2007; Geldner et al., 2003, 2001; Kitakura et al., 2011; Kleine-Vehn et al., 2010, 2008; Michniewicz et al., 2007). Substantially less is known about mechanisms that mediate conditional endocytosis and subsequent degradation of PIN proteins. Starting with observations on gravistimulated as well as dark-incubated seedlings, it became evident that a portion of PIN proteins appears to be internalized and sorted into the lytic vacuolar compartment (Abas et al., 2006; Kleine-Vehn et al., 2008; Laxmi et al., 2008). The phosphatidylinositol 3-kinase inhibitor wortmannin (WM) abolishes PIN2 trafficking to the vacuole (Kleine-Vehn et al., 2008), presumably by interfering with pre-vacuolar compartment (PVC) function (Oliviusson et al., 2006). Additional studies implicated further signals as modulators of PIN degradation via their targeting to the lytic compartment (Marhavy et al., 2011; Willige et al., 2011). However, mechanisms that signal endocytosis and degrada-

Fig. 3 – Model of posttranslational modifications of PIN proteins. (A) Phosphorylation as a binary switch for PIN polarity. PID-dependent phosphorylation leads to a basal to apical shift which can be counteract by PP2A activity. The place of PID and PP2A action is still not entirely elucidated but they partially localize to the plasma membrane. (B) Ubiquitylation as a trigger for endocytosis based trafficking. PIN proteins could either be non-ubiquitylated, mono- or poly-ubiquitylated. It is still unclear how the PIN ubiquitylation-status affects the PIN trafficking (endocytosis, recycling and/or degradation). PID, PINOID; PIN, PIN-FORMED; PP2A, PROTEIN PHOSPHATASE 2A; PVC, pre-vacuolar compartment; U, ubiquitylated.

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tion of plasma membrane proteins in plant cells are still poorly understood. In animals and fungi, the fate of endocytosed plasma membrane proteins is decisively influenced by reversible covalent modification with ubiquitin (Deribe et al., 2010; Hicke and Riezman, 1996; Kolling and Hollenberg, 1994; Lauwers et al., 2010; Terrell et al., 1998). A key role in preventing ubiquitylated cargo from either being recycled back to the plasma membrane or retained in endosomes has been attributed to the ENDOSOMAL SORTING COMPLEX REQUIRED FOR TRANSPORT (ESCRT) machinery. ESCRT is made up of distinct sub-complexes plus accessory proteins, which jointly control cargo sorting into multivesicular bodies (MVB) (reviewed in Henne et al., 2011; Raiborg and Stenmark, 2009; Roxrud et al., 2010; Schellmann and Pimpl, 2009). In plants, the localization of the ESCRT components VACUOLAR PROTEIN SORTING 28 (VPS28), VPS22, and VPS2 at the TGN/EE and PVC (the plant equivalent of MVBs) indicates that the formation of intraluminal vesicles starts already at the TGN/EE (Scheuring et al., 2011). This set of data suggests that the PVC/MVB might mature from the TGN/EE. Also components of the retromer complex have been detected both at the PVC/MVB and the TGN/EE (Jaillais et al., 2006, 2007; Niemes et al., 2010b; Oliviusson et al., 2006). The retromer complex consists of a SORTING NEXIN 1 (SNX1) dimer and a trimer of VPS26, VPS29 and VPS35 proteins (Bonifacino and Hurley, 2008). The SNX1 dimer tubulates the membrane, whereas the VPS trimer subcomplex is proposed to mediate the binding of the ligand (Bonifacino and Hurley, 2008; Collins, 2008; Seaman, 2005). In plants, the retromer complex regulates the balance between vacuolar degradation and recycling of PIN proteins (Kleine-Vehn et al., 2008) and functions either at the PVC/ MVB or at the TGN/EE where it could retain PIN proteins in the recycling pathway and, consequently, would reduce PIN protein transition to the vacuole. In addition, the retromer complex might also recycle vacuolar sorting receptors (VSR) from the TGN/EE to the ER (Niemes et al., 2010a), indicative of a role in diverse sorting pathways such as between the TGN/PVC and the TGN/ER (Fig. 2). Remarkably, a similar scenario has been suggested for animal cells, in which the mannose-6-phosphate receptor cycles (after release of ligands) between late endosomes and the TGN (Arighi et al., 2004; Carlton et al., 2004), while the Wntless receptor cycles retromer-dependent back to Golgi cisternae (Carlton et al., 2004).

9. Ubiquitylation in plants and its potential role for PIN degradation In plants, important insights into regulation of plasma membrane protein ubiquitylation and its role in protein endocytosis and sorting are just about to emerge. Data mining demonstrated a high degree of conservation for essential components of ESCRT complexes, and mutations in some of the corresponding gene products were found to have a profound impact on plant development and protein targeting (Ibl et al., 2011; Schellmann and Pimpl, 2009; Spitzer et al., 2009, 2006; Winter and Hauser, 2006). Of particular interest appear mutant combinations deficient in Arabidopsis

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CHARGED MULTIVESICULAR BODY PROTEIN1A/1B (CHMP1A/ 1B). Doa4-Independent Degradation2 (Did2), a yeast CHMP1 ortholog, has been implicated in modulating dissociation of ESCRT from endosomal membranes during late steps in MVB sorting (Nickerson et al., 2006). Similar functions have been suggested for Arabidopsis CHMP1-type proteins at the plant PVC/MVB (Spitzer et al., 2009). Strikingly, chmp1a chmp1b double mutant seedlings with highly pleiotropic phenotypes accumulate PIN1 and PIN2 reporter proteins both at the plasma membrane and the tonoplast, suggestive of deficiencies in ESCRT-mediated PIN sorting into lumenal PVC/MVB vesicles (Spitzer et al., 2009). Related deficiencies in endocytic sorting of PINs were suggested for mutants deficient in an Arabidopsis DEUBIQUITYLATING ENZYME (DUB) (Isono et al., 2010). In humans, ASSOCIATED MOLECULE WITH THE SH3 DOMAINE OF STAM (AMSH) and related proteins are required for deubiquitylation of endocytosed cargo, potentially essential for decisions leading to either retrieval or lysosomal targeting of cargo proteins, but definitely relevant for the recycling of ubiquitin molecules (Clague and Urbe, 2006). Similar to human AMSH (McCullough et al., 2006), Arabidopsis AMSH3 was demonstrated to hydrolyze K63-linked ubiquitin chains (Isono et al., 2010), raising the possibility that AMSH3 represents a true AMSH ortholog. Notably, AMSH3 interacts with VPS2.1 and VPS24.1 subunits of the ESCRT-III (Katsiarimpa et al., 2011), indicating a function in late endocytic targeting. Apart from highly pleiotropic phenotypes, affecting vacuole morphogenesis as well as protein transport, endocytic sorting from the plasma membrane appears deficient in amsh3 lossof-function mutants (Isono et al., 2010). In line with these observations, vacuolar accumulation of a PIN2-GFP reporter was abolished in amsh3 mutant lines, suggestive of a requirement of ubiquitin-hydrolyzing activities in PIN2 endocytic sorting (Isono et al., 2010). Besides these rather indirect indications for a role of protein ubiquitylation in PIN sorting or turnover, there is still very limited direct evidence for such a scenario. PIN ubiquitylation has so far been described only for PIN2 overexpression lines (Abas et al., 2006). Notably, treatment with the proteasome inhibitor MG132, results in apparent deficiencies in PIN2 endocytosis to the vacuole and in stabilization of ubiquitylated PIN2, implicating an -at least- indirect role for the proteasome-ubiquitin system in regulating PIN endocytosis and turnover (Abas et al., 2006; Laxmi et al., 2008) (Fig. 3B). It has to be stressed that neither PIN ubiquitylation sites nor types have been determined so far. This appears of particular interest, since ubiquitylated cargo has been described in Arabidopsis very recently, providing first insights into pattern and consequences of plasma membrane ubiquitylation in plants (Reyes et al., 2011). Site-directed mutagenesis and domain swapping experiments led to the identification of a lysine residue critical for ubiquitylation and stability of HIGH BORON REQUIRING 1 (BOR1) boron carrier protein (Kasai et al., 2011). This modification is seemingly triggered by elevated boron levels, which are suggested to cause either mono- or di-ubiquitylation of the carrier protein (Kasai et al., 2011). On the other hand, analysis of IRON-REGULATED TRANSPORTER 1 (IRT) iron carrier implicated mono-ubiquitylation-dependent endocytosis and vacuolar targeting, regardless of variations in iron availability (Barberon et al., 2011). In

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MECHANISMS OF DEVELOPMENT

addition, degradation of pattern recognition receptor FLAGELLIN SENSING 2 (FLS2) was found to be induced by flagellin-induced recruitment of U-box type E3-ligases PLANT U-BOX 12 (PUB12) and PUB13, which, in a phosphorylation-dependent manner, poly-ubiquitylate the cytosolic FLS2 domain in vitro (Lu et al., 2011). Moreover, analysis of Arabidopsis PHOTOTROPIN 1 (PHOT1) indicated both, mono- and poly-ubiquitylation, which depended on light intensity and was suggested to differentially affect PHOT1 fate, with mono-ubiquitylation promoting clathrin-dependent endocytosis, whereas polyubiquitylation would trigger PHOT1 degradation via the proteasome pathway (Roberts et al., 2011). Collectively, findings obtained from analysis of only a few selected plasma membrane proteins already suggested a high degree of variability in their respective ubiquitylation patterns. It remains to be determined in more detail, whether or not such diversity reflects actual differences in marking plasma membrane proteins for distinct sorting routes or degradation pathways (Reyes et al., 2011). Clearly, an elucidation of PIN ubiquitylation characteristics might strongly benefit from these findings, and could lead to practical models, addressing the role of different ubiquitylation modes and patterns in the control of PIN protein fate and auxin distribution (Fig. 3B).

10.

Phytohormonal control of PIN trafficking

In animals, hormones such as insulin or vasopressin can control the endocytosis and exocytosis rate of surface localized proteins like ion and water channels, transporters or receptors (Royle and Murrell-Lagnado, 2003). Similarly, auxin initiates feedback regulation on PIN-mediated cell-to-cell auxin transport by influencing the rate of PIN endocytosis (Paciorek et al., 2005). Auxin inhibits PIN internalization (visualized by BFA treatment) and the internalization of the endocytic tracer FM4-64 without affecting other subcellular trafficking processes (Paciorek et al., 2005). This process is mediated by TIR1/AFB independent mechanisms (Robert et al., 2010), and requires the auxin receptor ABP1 that affects PIN trafficking via impacting on the cytoskeleton (Xu et al., 2010) and by stimulating clathrin-dependent endocytosis (Robert et al., 2010). Auxin binding to ABP1 interferes with ABP1-induced endocytosis, providing a mechanistic explanation for the inhibitory effects of auxin on endocytosis (Paciorek et al., 2005; Robert et al., 2010). It has to be mentioned that Pan and coworkers suggested that auxin-mediated inhibition of endocytosis does involve activity of TIR1/AFB-type of auxin receptors (Pan et al., 2009), which differs from the observations made with ABP1 (Robert et al., 2010) (Fig. 4). Variations in experimental conditions might account for these discrepancies. Noteworthy, auxin seemingly has dual functions in regulating PIN fate, exhibiting inhibitory effects on endocytosis as well as promoting proteolytic turnover of PINs upon extended incubation in presence of the growth regulator (Abas et al., 2006; Robert et al., 2010; Sieberer et al., 2000). Disentangling the consequences of these antagonizing effects on PIN protein fate remains subject of further experimentation. Next to auxin, additional hormones like cytokinin, methyl jasmonate (MeJA) and gibberellic acid (GA) contribute to the

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Fig. 4 – Hormonal contribution to the regulation of PIN trafficking. The TGN/EE crystallizes as a main sorting hub for arriving and departing cargos. This sorting framework (retention/recycling versus degradation/vacuolar targeting) is under phytohormonal control. Auxin, jasmonate, gibberellin and cytokinin either act on PIN retention (blue arrows) or degradation (green arrows). However, both the signal perception and molecular mode of action on the level of vesicle trafficking largely remains to be unraveled. ABP1, AUXIN BINDING PROTEIN 1; AHK4, ARABIDOPSIS HISTIDIN KINASE 4; COI1, CORONATINE INSENSITIVE 1; GID1, GIBBERELLIN INSENSITIVE DWARF 1; TGN/EE, trans-Golgi network/early endosome; TIR1, TRANSPORT INHIBITOR RESISTANT1.

regulation of the endocytic PIN trafficking. For instance, cytokinin is involved in the regulation of PIN1 targeting to the lytic vacuole for degradation. This PIN1 specific regulation occurs downstream of the known cytokinin receptor CYTOKININ RESPONSE 1/ARABIDOPSIS HISTIDIN KINASE 4 (CRE1/AHK4) and has a functional relevance for plant organogenesis (Marhavy et al., 2011). Furthermore, CORONATINE INSENSITIVE 1 (COI1)-dependent perception of methyl jasmonate (MeJA) was demonstrated to affect PIN2 abundance. At low concentrations MeJA inhibits PIN2 endocytosis, whereas high MeJA concentrations reduce the PIN2 protein amount at the plasma membrane (Sun et al., 2011). Strikingly, MeJA effects on PIN2 endocytosis requires TIR1-induced ANTHRANILATE SYNTHASE a1 (ASA1)-dependent auxin biosynthesis (Sun et al., 2011). In contrast, effects of high MeJA concentrations on PIN2 turnover occur independently of TIR1 perception (Sun et al., 2011). Another report demonstrated that GA perception via GIBBERELLIN INSENSITIVE DWARF 1 (GID1) decreases PIN2, but not AUX1 targeting to the vacuole for lytic degradation (Willige et al., 2011). This regulation might have functional importance for fine-tuning gravitropic root growth (Willige et al., 2011). However, it remains to be clarified as to how GA could regulate PIN2 trafficking. A number of experimental studies now support a scenario in which regulation of PIN protein abundance via intrinsic and environmental cues represents a universal signaling module that orchestrates the rate of PIN-dependent polar auxin transport. This implies cross-talk between various signaling pathways, thereby modulating PIN protein levels in a spatiotemporal context, which seems essential for a range of developmental responses.

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MECHANISMS OF DEVELOPMENT

11.

Concluding remarks

Plants evolved a remarkable phenotypic plasticity. Changes in auxin levels and signaling are tightly connected to the flexible nature of plants. Many of these changes require differential regulation of vesicle trafficking, ultimately inducing alterations in PIN polarity and/or abundance. Increasing evidences suggest that most intracellular protein (re)-sorting occurs at the TGN/EE (Dettmer et al., 2006; Viotti et al., 2010). It remains to be seen how the TGN/EE masters and differentiates between non-polar secretion, polar recycling or targeting to the vacuole. One possibility is the formation of distinct sub-populations or sub-compartments at the TGN/ EE (Fig. 2). Intriguingly, drugs like BFA, Endosidin 1 (ES1), concanamycin A (ConA) interfere all with TGN/EE function (Geldner et al., 2003; Dettmer et al., 2006; Robert et al., 2008), but exert distinct effects on PIN trafficking, which might support the idea of different TGN/EE sub-populations or sub-compartments. It is possible that PIN phosphorylation and ubiquitylation affects PIN sorting at the TGN/EE, leading either to polar recycling or transit to the lytic vacuole. Furthermore, accumulating experimental evidence suggests that complex phytohormonal crosstalk orchestrates auxin transport via regulation of PIN trafficking (Marhavy et al., 2011; Robert et al., 2010; Sun et al., 2011; Willige et al., 2011). Auxin, jasmonate, gibberellin and cytokinin jointly regulate PIN stability. Whereas auxin (and jasmonate via auxin biosynthesis) appears to regulate PIN endocytosis, most sites and pathways that mediate hormonally controlled vacuolar PIN targeting remain largely unknown. It is tempting to speculate that these phytohormones in part affect PIN trafficking via posttranslational PIN modification. Further research is needed to fully depict the PIN trafficking routes and the consequences of posttranslational modifications, such as PIN phosphorylation and ubiquitylation. While reversible PIN phosphorylation seemingly affects alternative PIN recruitment to distinct polar targeting pathways, it remains to be seen whether PIN ubiquitylation similarly leads to a differential recruitment to endocytic targeting pathways.

Acknowledgments This work was supported by Grants from the Vienna Science and Technology Fund (WWTF) (to J.K.-V.) and by FWF Grant P19585 (to C. Lu.). We thank Elke Barbez and Thomas Teichmann for critical reading of the manuscript. We apologize to our colleagues whose work have been inadvertently omitted or could not be reviewed in depth.

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