Cajal bodies (CBs) are small nuclear structures present in metabolically active mammalian cells, especially neurons, where their size is often increased compared to other cell types [27]. They are characterized by the presence of the two main components, the p80 coilin and the survival motor neuron (SMN) protein. CBs are involved in the processing of replication-dependent histone mRNAs and in the biogenesis of ribonucleoproteins associated with pre-mRNA, pre-rRNA processing and splicing [27].

CBs are transcription-dependent and high numbers of Cajal bodies are indicative of a transcriptionally active cell with a high cellular mass [28]. SUMO1 and Ubc9 transiently co-localize to Cajal bodies in undifferentiated neuron-like UR61 cells [29]. Although not yet validated as SUMO substrates, both coilin and SMN possess high probability SUMOylation sites and coilin interacts with the SUMO E3 ligase PIASγ [30]. Interestingly, this association occurs only in undifferentiated cells and cells that have been exposed to stress [29]. Therefore, it has been hypothesized that SUMO1 translocation to CBs is dependent on events during neuronal differentiation and forms part of a stress response in differentiated cells. These results are consistent with reports that changes in protein SUMOylation play an important role in neuronal development and survival [8,31,32,33]. Hence, it seems likely that CBs represent a potential target of neuroprotection by SUMOylation.

Another nuclear structure abundant in SUMO is the PML body, which are highly enriched in the promyelocytic leukemia (PML) protein. SUMOylation is prerequisite for the PML body formation since only SUMOylated PML is able to recruit other PML body proteins such as Daxx [9,10,34]. PML bodies are involved in a variety of processes including viral defense, stress response and genome stability [35,36,37]. Although PML bodies appear to be absent from most neurons [38,39] they are present in human dorsal root ganglion neurons (DRGN) [40]. Interestingly, in DRGNs affected by acute inflammatory demyelinating polyneuropathy (AIDP) associated with Guillain-Barre syndrome [41], the number of PML bodies increases with the severity of the dymyelination [40]. Thus, PML bodies are potentially involved in the DRGN response to axonal damage and injury. This is supported by the finding that in AIDP neurons, the glucocorticoid receptor (GR), itself a SUMO substrate, is localized to PML bodies, whereas in healthy cells GR does not localize to any nuclear foci [42,43]. This re-localization might play a role on the transcriptional regulation of genes expressed upon axonal damage.

All organisms are affected by a circadian rhythm, which spans a period of about 24 hours [44]. In mammalians, the circadian rhythm is regulated by a master clock in the suprachiasmatic nuclei of the hypothalamus which is entrained by the natural light-dark cycles [44,45]. Disruption of the circadian rhythm can be involved in bipolar disorder, sleeping disorders and dementia [45]. The transcription factor BMAL1 is an essential component of the clock [44,46] and can be SUMOylated by SUMO1, SUMO2 or SUMO3 [11,12]. Under physiological conditions, BMAL1 is predominantly modified by SUMO2/3, which is involved in the localization of BMAL1 to PML bodies where it functions as a transcription factor [11]. In addition, SUMOylation also triggers ubiquitin-mediated periodic degradation of BMAL1 at PML bodies [11,12]. Although SUMOylation has been thought to antagonize proteasomal degradation of proteins, the discovery of SUMO-targeted ubiquitin ligases (StUbls) has shown that SUMO and ubiquitin can collaborate to promote protein degradation [47]. StUbls are present at PML bodies [48] so it is likely that an as yet unidentified StUbl regulates BMAL1 SUMOylation and degradation.

The activity-dependent removal and insertion of AMPA receptors from and into the post-synaptic membrane underlies long-term depression (LTD) and long-term potentiation (LTP) [49,50]. Although AMPA receptors themselves do not appear to be SUMO substrates [19], synaptic SUMOylation has been implicated in LTP [51]. For example, glycine-induced chemical LTP leads to an increased co-localization of Ubc9 and SUMO1 in dendrites [52], suggesting activity-dependent loading of Ubc9 with SUMO. A possible SUMO target known to regulate AMPA receptor surface expression is the activity-related cytoskeletal-associated protein Arc/Arg3.1 [18]. It has been suggested that SUMOylation causes Arc to relocate into dendrites [18] where interaction of Arc with the cytoskeleton is involved in the establishment and maintenance of LTP and synaptic scaling [7,18].

Kainate receptors (KARs) play important roles in the regulation of synaptic transmission and neuronal excitability [53,54,55,56]. The KAR subunit GluK2 is SUMOylated in response to agonist stimulation, which leads to endocytosis of GluK2-containing kainate receptors [19]. Although both, kainate and NMDA-stimulation, lead to KAR internalisation, NMDA-induced endocytosis does not involve GluK2 SUMO modification [19]. Agonist-induced or NMDA-induced endocytosis events are respectively associated with GluK2 degradation or recycling [57]. Thus, it is tempting to speculate that SUMOylation might target GluK2 towards lysosomal degradation following endocytosis, whereas non-modified GluK2 is recycled and can be subsequently re-inserted into the membrane.

More recently, details of how SUMOylation of GluK2 is regulated and the importance of this modification for KAR plasticity have emerged. It has been shown that kainate stimulation leads to PKC-mediated phosphorylation of GluK2 which, in turn, promotes its SUMOylation and internalization [58]. Notably, this phosphorylation-mediated SUMOylation of GluK2 is required for the removal of GluK2-containing KARs during KAR LTD at mossy fibre synapses [59], providing the first direct example of a requirement for SUMO-mediated protein trafficking in a form of synaptic plasticity (Figure 2a).

The group III family of metabotropic glutamate receptors (mGluRs) comprises mGluR4 and mGluR6-8 [60]. They are expressed throughout the brain and, with the exception of mGluR6, are mostly presynaptic at glutamatergic and GABAergic terminals, where they act to regulate presynaptic release [60]. In yeast two-hybrid assays the c-termini of mGluR8a and 8b interact with Ubc9 and SUMO1, in addition to the SUMO E3 ligases PIAS1, PIASγ, PIASxβ. Subsequently, it was shown that PIAS1 interacts with the c-termini of all group III mGluRs [21] and that the mGluR8 c-terminus can also interact with the E3 ligases Pc2 and PIAS3L [20]. In addition, full-length mGluR8b can be SUMOylated in HEK293 cells co-transfected with SUMO1 [20].

However, despite these data, no direct co-immunoprecipitation of SUMOylated endogenous mGluRs from neurons or brain has yet been achieved and the functional consequences of mGluR SUMOylation remain to be determined. Because of this it has been questioned if group III mGluRs are actually true SUMO targets. For example, although mGluR7 is SUMOylated at a specific lysine residue in vitro, SUMO modification in neurons was not detected and no functional or trafficking differences were observed upon over-expression of a non-SUMOylatable mutant of mGluR7 [61]. Thus, while it remains possible that endogenous mGluRs do undergo SUMOylation, the number of receptors SUMOylated at any given time may be very small and the functional consequences very subtle.

The cannabinoid receptor 1 (CB1) is the most widely-expressed G-protein coupled receptor in the brain [62]. CB1 is distributed largely presynaptically and, upon agonist activation, acts to suppress neuronal excitability and neurotransmitter release through coupling to G_i and G_o G proteins [63]. In primary rat cortical neurons the CB1 agonist Δ9-THC has been reported to increase levels of un-conjugated SUMO1, an effect blocked by the selective CB1 antagonist AM251. The authors propose that some of this increase in free SUMO1 derives from de-SUMOylation of CB1 and the tumor suppressor p53 following treatment with Δ9-THC [22] and that de-SUMOylation of CB1 causes its internalization while de-SUMOylation of p53 hinders its nuclear export [22,64]. Further validation is required but these observations would suggest that CB1 is unusual in being highly SUMOylated under basal conditions, in contrast to the vast majority of reported SUMO substrates, and that its trafficking and translocation are induced by activity-dependent deSUMOylation.

It is well-established that local protein translation occurs in axons and dendrites [65]. This requires the packaging of mRNAs and components of the translation machinery into granules and transport to designated translation sites [66]. The RNA-binding protein La recognizes RNA transcripts containing a 5’-UTR terminal oligopyrimidine (TOP) element and acts as an RNA chaperone during transport [67]. Neurons express several mRNAs containing the TOP motif, including the known La target grp78/BiP [68].

La can move along the microtubule network in retrograde or anterograde directions by binding dynein or kinesin, respectively [23]. SUMOylation of La appears to be the switch that determines the direction of La transport. SUMOylated La only binds to dynein and therefore is subject to retrograde transport towards the nucleus. Conversely, non-SUMOylated La binds kinesin and undergoes anterograde transport [23]. This is an intriguing observation and further work should define if SUMOylation might act as a general switch that can determine the polarity of target protein transport (Figure 2b).

The serine/threonine kinase GSK3β plays a central role in many cell pathways including energy metabolism, Wnt signalling, neuronal development, inflammation, tumorigenesis and cell death [69,70,71,72]. In neurons, GSK3β has been reported to be involved in regulating the balance between LTP and LTD [73] and has been implicated in a number of neurodegenerative disorders. Like many of the proteins it phosphorylates, GSK3β can be SUMOylated [13]. Wild type GSK3β is present throughout the cytoplasm and nucleus whereas a SUMOylation-deficient GSK3β mutant is excluded from the nucleus and present only in the cytoplasm [13]. It remains to be established if deSUMOylated GSK3β is actively exported from the nucleus or if the SUMO moiety acts as a nuclear localization signal. Whatever the mechanism, it appears again that SUMOylation acts as a switch to bring about translocation/re-localization of the substrate protein, potentially playing a central role in synaptic plasticity and neuronal function.

FAK is an important mediator of signals between the extracellular matrix and the cytoplasm and is involved in controlling cell motility, shape and adhesion [74,75]. In neurons, FAK is important for neuronal migration and axon pathfinding [76,77,78]. FAK autophosporylates at Tyr397 to create a binding site for interaction partners including other kinases such as Src and Fyn [79]. SUMOylation of FAK at Lys152 increases autophosphorylation and promotes its nuclear localization [17,80]. However, the nuclear function of FAK remains unclear and further work is required to define how this nucleo-cytoplasmic shuttling of FAK is mediated.

The caspase family of cysteine proteases mediate apoptotic neuronal death [81] but members of this family have also been reported to play physiological roles in AMPA receptor trafficking and synaptic plasticity [82]. In general, caspases can be divided into two subgroups, namely the initiator caspases and the effector caspases. Members of both subgroups have been reported to be SUMOylated, which promotes their nuclear localization [14,15,16]. Caspase-2 and caspase-7 are localized in nuclear speckles, identified as PML bodies for caspase-2 [15,16], whereas caspase-8 shows a more dispersed nuclear distribution [14]. It has been hypothesized that this translocation of caspases to the nucleus acts on specific targets in circumstances of cell stress such as neuronal hypoxia in the brain [15]. Interestingly, among the caspases there is no common domain containing the putative SUMOylation site. For the initiator caspases the SUMOylation sites are located within the death effector domain or the caspase recruitment domain [14,16] but the SUMOylation site of the effector caspase-7 is within the p20 subunit of the activated caspase [15]. As yet, very little functional data has been reported but SUMOylation of caspase-2 appears to increase its maturation from procaspase-2 [16]. Clearly, there is plenty of potential for future investigation.