Ubiquitin Proteasome System-Mediated Degradation of Synaptic Proteins: an Update from the Postsynaptic Side

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Biochimica et Biophysica Acta 1843 (2014) 2838–2842

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Review Ubiquitin proteasome system-mediated degradation of synaptic proteins: An update from the postsynaptic side

Nien-Pei Tsai ⁎

Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA

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Article history: The ubiquitin proteasome system is one of the principle mechanisms for the regulation of protein homeostasis in Received 5 July 2014 mammalian cells. In dynamic cellular structures such as neuronal synapses, ubiquitin proteasome system and Received in revised form 10 August 2014 protein translation provide an efﬁcient way for cells to respond promptly to local stimulation and regulate Accepted 11 August 2014 neuroplasticity. The majority of research related to long-term plasticity has been focused on the postsynapses Available online 16 August 2014 and has shown that ubiquitination and subsequent degradation of speciﬁc proteins are involved in various

Keywords: activity-dependent plasticity events. This review summarizes recent achievements in understanding Ubiquitination ubiquitination of postsynaptic proteins and its impact on synapse plasticity and discusses the direction for Synapse advancing future research in the ﬁeld. E3 ligase © 2014 Elsevier B.V. All rights reserved. Plasticity Proteasome Neuronal activity

1. Introduction the central nervous system such as ischemia or hypoxia [6,7],and neurodegenerative diseases [8–10], this review will primarily focus on Synapses and synapse plasticity play critical roles in determining ubiquitination-mediated degradation of synaptic or synapse-related the connectivity and strength of the neural circuit. Multiple layers of proteins in physiological conditions. Due to the increased number regulation provide efficient management of synaptic transmission of recent studies showing activity-dependent regulation of UPS at during neural development and in response to stimulation (activity). postsynapses, the focus of this review will be on the events that occur The regulation that takes place locally, at or near the synapses, has in postsynapses. received tremendous attention in the past decade. This is mainly because regulation at the local level provides not only a quicker 2. Proteasome and protein ubiquitination response to stimulation but also the specificity and selectivity for regulation of different neurons, axons, dendrites, and even synapses [1–5]. In eukaryotic cells proteasomes are protein complexes whose Local regulation can be divided into two categories based on whether function is to degrade misfolded proteins and certain other proteins it affects protein content. 1) Regulation that does not affect protein con- destined to be eliminated [11]. A small regulatory protein known as tent can occur through signaling cascades to mediate protein–protein ubiquitin is covalently linked to proteins that are to be degraded interaction, protein trafficking, and posttranslational modifications by the proteasome. This tagging reaction, which is called protein (except for ubiquitination). 2) Regulation that affects total or specific ubiquitination, is triggered by a series of enzymatic reactions (Fig. 1). protein content can occur through local protein translation or turnover. Initially, E1 ubiquitin-activating enzyme binds to a ubiquitin molecule Of these, local protein turnover has not been well studied but is emerg- and then catalyzes a reaction to link ubiquitin onto E1 through a ing as an important field. This is particularly true for proteasome- thioester linkage. Secondly, E2 ubiquitin-conjugating enzyme transfers mediated degradation, as the ubiquitin proteasome system (UPS) the ubiquitin from E1 to an active site on E2 through a transes- provides spatial and target-specific degradation, which are ideal for terification reaction. Finally, E3 ligase, which interacts with both the dynamic and heterogeneous compartments such as synapses. Although substrate and E2, catalyzes the transfer of ubiquitin from E2 to the UPS is strongly associated with many pathophysiological conditions in substrate [11]. Currently several hundred E3 ligases have been identified; substantially these provide the specificity of ubiquitination for particular proteins. ⁎ Department of Molecular and Integrative Physiology, School of Molecular and Cellular Many studies have elucidated the importance of proteasomes in reg- Biology, University of Illinois at Urbana-Champaign, 407 South Goodwin Ave., Urbana, IL – 61801, USA. Tel.: +1 217 244 5620; fax: +1 217 333 1133. ulating functional and structural synapse plasticity [3,12 18]. It is not E-mail address: [email protected]. surprising that efforts to better understand the role of proteasomes

regulated indirectly by ubiquitination through the Wiskott-Aldrich syndrome protein (WASP) family member WASH-dependent mechanism [28]. Therefore, it would be an important topic to understand whether F-actin level and polymerization at synapses can also be regulated by ubiquitination-related mechanisms as that would likely in turn affect synapse plasticity. Besides cytoskeleton proteins, scaffold proteins are another group of structural components in PSD that have the ability to affect the structure and complexity of PSD depending on their protein interaction network. Among several PSD-associated scaffold proteins regulated by UPS, PSD-95 is of particular interest because it is the best studied member of the membrane-associated guanylate kinase (MAGUK) family of PDZ domain-containing proteins [29].Thefirst study that identified PSD-95 as being poly-ubiquitinated linked it to NMDA-induced AMPA-receptor endocytosis [30]. This report also identified the ubiquitin E3 ligase specific for PSD-95 as murine double minute-2 (Mdm2), the well-known E3 ligase widely studied for its role in ubiquitinating the tumor suppressor p53 and regulating tumor- Fig. 1. The general ubiquitination pathway. The pathway starts with an ATP-dependent igenesis [31]. Additionally this study reported a potential PEST sequence activation of Ubiquitin (Ub) by an E1 ubiquitin-activating enzyme (E1). An E2 (a peptide sequence linked to protein degradation that is rich in conjugating-enzyme (E2) then catalyzes the transfer of a ubiquitin from an E1 to an E2. When a substrate is brought by an E3 ligase (E3) to a Ub-conjugated E2, the Ub is proline, glutamic acid, serine, and threonine) [32] in Mdm2-mediated transferred to the substrate on specific lysine residues. Depending on the functional ubiquitination; however, the function of this sequence in neuronal domain in E3 ligases, this step can be a direct Ub transfer from E2 to the substrate or a cells is currently unconfirmed. This is primarily because the PEST- two-step process involving a transient binding of E3s to the Ub. As this same deletion mutant of PSD-95 showed an abnormal dendritic distribution ubiquitination pathway repeats, a protein substrate can be poly-ubiquitinated. [33] and could not be used for studying the physical contact between PSD-95 and Mdm2 under physiological conditions. Despite this, the have been focused on the identification of E3 ligases and the substrates fact of PSD-95 ubiquitination is not in doubt as many follow-up studies involved in synapse plasticity, since this is the rate-limiting step during have confirmed this observation and suggested several regulatory protein ubiquitination as well as the step where specificity comes into mechanisms underlying Mdm2-mediated PSD-95 ubiquitination. play. Several studies have linked different E3 ligases to the regulation These include the action of cyclin-dependent kinase 5 (Cdk5) [34], of synapse plasticity and the associated animal behavior [19–21]. the level of lipoprotein receptor LRP1 [35], and the activation of Studies have also uncovered ubiquitinated proteins in postsynapses by activity-dependent transcription factor myocyte enhancer factor 2 both candidate-based [22] and unbiased proteomic approaches [23] (MEF2) [36]. The latter study also connected Mdm2-mediated PSD-95 (Table 1). However, because of the number of E3 ligases and all their ubiquitination to the deficiency in activity-dependent synapse elimina- possible substrates, linking the critical E3 ligase and its substrate to tion observed in the mouse model of fragile X syndrome (FXS), the most synapse plasticity is still considered an understudied subject. common genetic form of mental retardation and autism [37,38]. Another important scaffold protein known to be ubiquitinated is 3. Ubiquitination of postsynaptic scaffold proteins Homer1a. Homers are a family of scaffold proteins with 3 major isoforms (Homer1, Homer2, and Homer3), which are thought to medi- The postsynaptic density (PSD) is a complex of proteins localized in ate synapse signaling and are involved in learning and memory [39]. the postsynaptic membrane that provides functional and structural Although Homers are known to be associated with UPS [40],thus support for excitatory synaptic transmission [24]. The size, integrity, far, Homer1a is the only isoform that has been confirmed as being and content of PSD are known to affect the strength of the synaptic ubiquitinated [40–42]. Homer1a, a short splice variant of Homer1, transmission [24]. The cytoskeleton protein is one of the major groups lacks a coiled-coil domain for oligomerization [43] and has been of components identified in the PSD [25]. Among those identified, suggested to be a competitor of full-length Homers in multiple signaling the filament actin (F-actin) plays the most critical role in mediating pathways [43,44]. The ubiquitination of Homer1a occurs at an 11-amino dendritic spine morphology and function [26,27]. Although it is unclear acid region in its C-terminal end [42] and is thought to play a role in whether F-actin can be ubiquitinated, F-actin polymerization can be synapse plasticity [45]. The ubiquitination of other Homers has not yet been confirmed; however, given the number of Homers known to be associated with synapse plasticity and related behavioral tests [46,47], Table 1 it is highly possible that UPS-mediated turnover occurs with other The summary of ubiquitinated proteins in the postsynapses described in this article. Homer family members. Postsynaptic protein Protein name E3 ligase Associated Other PSD proteins reportedly regulated by UPS include Shank [22], fi category identi ed references GKAP [22,23,48], and AKAP79/109 [22]. The ubiquitination and the Scaffold protein PSD-95 Mdm2 [30,33–36] subsequent levels of Shank, GKAP, and AKAP79/109 were shown to all Homer1a [40–42] be regulated in a similar fashion by neuronal activity [22]. Treatment Shank [22] of cortical neuronal cultures with tetrodotoxin (TTX), an inhibitor GKAP Trim3 [22,23,48] fi AKAP79/109 [22] of neuronal action potential ring, reduced the ubiquitination and Receptor protein/subunit AMPAR (GluA1 subunit) Nedd4-1 [52] increased the levels of all three proteins; whereas, treatment of the AMPAR (GluA2 subunit) [53] cultures with bicuculline, an antagonist of γ-aminobutyric acid NMDAR (NR2B subunit) Mib2 [57] (GABA) receptor A, GABA(A) receptor, resulted in the reverse effect. mGluR1a Siah1a [40,58] mGluR5 Siah1a [58] However, these manipulations of neuronal activity produced completely GABA(A) [59,60] opposite effects on other scaffold proteins, such as PSD-95 and Homers Signaling molecule Arc Ube3a, Triad3a [67–70] [22,36,45]. This differential regulation suggests that the activity- CaMKII [23] induced ubiquitination of scaffold proteins might occur differently in SPAR β-TRCP [76] different regions within the PSD, such as the region closer to the 2840 N.-P. Tsai / Biochimica et Biophysica Acta 1843 (2014) 2838–2842 member where PSD-95 primarily locates and the region closer to cyto- triggering and being activated by various signaling cascades, it would plasm where Shank is concentrated [49]. This scenario will suggest an be of particular interest to understand 1) under what circumstances activity-dependent rearrangement of PSD structures within the same mGluRs are ubiquitinated and 2) what the consequences of the synapse. A real-time, imaging-based experiment to determine the ubiquitination of mGluRs are. level of these scaffold proteins in synapses during activity manipulation Another postsynaptic receptor known to be ubiquitinated is the might give us an insight into how scaffold proteins are differentially GABA(A) receptor. GABA(A) receptor is the major ligand-gated ion regulated. channel that mediates fast synaptic inhibition. A study has shown that chronic inhibition of neuronal activity increases the level of the 4. Ubiquitination of neurotransmitter receptors GABA(A) receptor ubiquitination and reduces its cell surface stability, while increasing neuronal activity results in reverse effects [59]. Along Neurotransmitter receptors at the postsynaptic cells are the main with the same logic, the trafficking of GABA(A) receptor subunit into players in regulating synaptic transmission. Multiple receptors have lysosome for degradation is also regulated by ubiquitination [60].This been identified in an unbiased screening for ubiquitinated proteins regulation occurs particularly in the intracellular domain of the γ2 [23]. Among them, glutamate receptors are of particular interest subunit. In summary, these data provide another mechanism to regu- due to their importance for synapse plasticity and their role in late synapse plasticity through ubiquitination on neurotransmitter neurodevelopmental and psychiatric disorders. Consequently, the regu- receptors. lation of glutamate receptors by ubiquitination has become a focus of study. 5. Ubiquitination of other signaling molecules One of the most well-known glutamate-gated receptors is the AMPA receptor, which mediates fast synaptic transmission. The insertion and Synapse plasticity is regulated by various signaling pathways removal of AMPA receptor subunits are two of the major mechanisms especially in neuronal activity events. Among many signaling molecules involved in synaptic strength and are considered the most well- regulated by UPS, three proteins are currently attracting much attention studied mechanism in long-term synapse plasticity [50,51]. A study to due to their importance at the postsynaptic terminals. The first is the determine if ubiquitination can mediate the functions of the AMPA activity-regulated cytoskeleton-associated protein (Arc) [61]. It is well receptor showed that the AMPA receptor subunit GluA1 is ubiquitinated known that Arc facilitates the internalization of AMPA receptors during AMPA-triggered neuronal activity [52]. The same study also [62,63]. Because of this, the level of Arc has been directly implicated in demonstrated that this ubiquitination most likely occurs at the lysine- many synapse-weakening processes, including in synaptic long-term rich region of the GluA1 C-terminus and involves the E3 ligase depression (LTD) [62,63] and synapse elimination [64].Ube3Awasthe known as the neural-precursor cell-expressed developmentally down- first ubiquitin E3 ligase identified for Arc. Back in the late 1990s, studies regulated gene 4-1 (Nedd4-1). Most importantly, this particular showed that the loss of a maternal copy of the UBE3A gene accounts for ubiquitination event regulates the endocytic properties of GluA1- over 80% of Angelman Syndrome cases, a severe neurodevelopmental containing AMPA receptors rather than leading to direct protein degra- disorder [65,66]. During the past 5 years, multiple studies proposed dation. A subsequent study revealed that promoting neuronal activity, that dysregulation of the AMPA receptor level in synapses triggered by by using either the GABA-A receptor antagonist or AMPA receptor abnormal Arc ubiquitination might lead to the symptoms seen in agonist, induces ubiquitination of the GluA2 subunit of the AMPA recep- Angelman Syndrome [67,68]. However, recent studies questioned if tor and subsequently leads to receptor endocytosis [53]. Although Ube3A is the most critical E3 ligase for Arc [69,70]. The second ubiquitin multiple studies have demonstrated ubiquitin-mediated regulation of E3 ligase identified for Arc is the RING domain ubiquitin ligase Triad3A membrane proteins in neuronal cells [54–56], the AMPA receptor is [69]. In Triad3A-knockdown cells, Arc is accumulated, and the level of the first postsynaptic receptor whose endocytosis has been shown to the surface AMPA receptor is reduced accordingly. Because of the role be regulated by ubiquitination. of Arc in activity-dependent synapse plasticity, Triad3A, therefore, Another critical glutamate-gated ion channel is the NMDA receptor. appears to act as a terminator for Arc-mediated events during neuronal Upon activation, NMDA receptor is permeable by several ions, including activity. calcium. The influx of calcium into postsynaptic cells initiates a number Another signaling protein ubiquitinated at the postsynaptic of signaling cascades that are important for synapse plasticity and terminal is Ca2+/calmodulin-dependent protein kinase II (CaMKII) memory-related processes. Therefore, much effort has been applied to [23]. CaMKII regulates synapse plasticity at postsynaptic terminals understanding the regulation of NMDA receptor functions, including through various mechanisms, including phosphorylating the subunits posttranslational modifications. Several different regulatory mecha- of AMPA and NMDA receptors [71,72], acting as a scaffold component nisms have been identified thus far. It was recently reported that at PSD [73,74], and regulating proteasome movement into dendritic the NR2B subunit of the NMDA receptor can be ubiquitinated by the spines [2,75] (discussed later). Although both the identity of the E3 E3 ligase Mind bomb-2 (Mib2) [57]. Although it is unclear if the ligase specific for CaMKII and the consequences of the ubiquitination ubiquitination of NR2B leads to receptor endocytosis, degradation, or of CaMKII are still unclear, exploring the effects of CaMKII ubiquitination other downstream signaling cascades, the same study demonstrated in synapse plasticity is an important research direction, especially given the possibility that ubiquitination can regulate the function of the the diverse roles played by CaMKII at the synapses. NMDA receptor. The final postsynaptic signaling molecule being ubiquitinated is the In addition to the ionotropic glutamate receptors, such as the AMPA spine-associated Rap guanosine triphosphatase activating protein and NMDA receptors, the metabotropic glutamate receptors (mGluRs) (SPAR) [76]. SPAR is an actin regulatory protein that is critical for are also critical for synapse plasticity, especially in the case of long- controlling dendritic spine morphology. Upon neuronal activity stimu- term depression (LTD). Among the members of two groups of mGluRs, lation, SPAR is phosphorylated by polo-like kinase 2 (Plk2) [77,78], group 1 and 2, two members of group 1 have been reported to which leads to SPAR ubiquitination and degradation, and subsequent be ubiquitinated. A study found that the ubiquitin E3 ligase Seven in synapse weakening [76,78].Theβ-Transducin Repeat Containing absentia homolog 1A (Siah1a) can ubiquitinate both mGluR1a and Protein Ligase (β-TRCP), one of the four subunits in Skp1/Cul1/F-box mGluR5, which leads to their proteasome degradation [58]. A follow- protein (SCF) complex, is identified as the E3 ligase responsible for up study indicated that such ubiquitination, especially of mGluR1a, SPAR ubiquitination. Because of the indispensable functions of SPAR in requires the long isomer Homer3 as a shuttling protein to bring regulating dendritic spine morphology, the ubiquitination of SPAR ubiquitinated mGluR1a to the proteasomes through interaction with has important implications for affecting synapse plasticity, such as the proteasome component S8 ATPase [40]. Because mGluRs are both homeostatic synapse plasticity [77–79]. N.-P. Tsai / Biochimica et Biophysica Acta 1843 (2014) 2838–2842 2841

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