MATERIAL AND METHODS
6. Is cytoplasmic E1 a prerequisite for cytoplasmic SUMOylation?
ar
2 homolog from The amount of E1 in the cytoplasm is usually very small compared to the nucle pool. In light of the fact that SUMOylation is an essential cellular process, the differences in the levels of E1 enzyme raised the fundamental question, whether the E1’s intracellular distribution is important for cells. Possibly, the vast amount in the nucleus may be needed for nuclear SUMOylation or cells may only tolerate low amounts of E1 in the cytoplasm to avoid unspecific SUMOylation.
A previous study by the laboratory of Dohmen on the Uba
Saccharomyces cerevisiae revealed that a fragment of S.c.Uba21-554 lacking 82 amino acids at the C-terminus, overexpressed under Gal1-promoter, is able to rescue the deletion of endogenous UBA2, even though the fragment mislocalized to the cytoplasm (Dohmen et al. 1995). A more sensitive phenotypic analysis of the S.c.Uba21-602 fragment under the control of the natural UBA2 promoter was performed in the laboratory of Lima. Expression of the fragment that only lacked the last 34 residues of S.c.Uba2 (including both basic clusters according to the mapped NLS in human Uba2) fully rescued the deletion of endogenous UBA2 gene but resulted in slightly altered Smt3 conjugation pattern of cell lysate (Lois et al. 2005). In contrast to these studies, Del Olmo and his co-workers observed that partial
disruption of the UBA2 gene, resulting in S.c.Uba21-594 - a fragment lacking 42 C-terminal residues, leads to a 2fold slower growth and larger cells compared to wild type yeast strains (del Olmo et al. 1997).
In line with the previous findings by Dohmen and Lima, the data obtained with the
1 does indeed not
E2 NLS-mutant S.c.Uba2-∆NLS strongly suggest that a predominant cytoplasmic localization of the E1 does not alter the viability of yeast under normal or stress conditions (Fig. 33, 34). However, even the variant S.c.Uba2-∆NLS-NES, which contained a disrupted NLS and an additional NES, was partially detected in the nucleus of cells (Fig. 32). In line with this finding, the study of Dohmen demonstrated that the C-terminal deletion fragment of S.c.Uba2, which lacked both basic clusters corresponding to the mapped NLS in H.s.Uba2, localized to both nucleus and cytoplasm (Dohmen et al. 1995). Therefore it can be assumed, that a partial nuclear localization of Uba2 very likely also underlied the studies by Lima and Del Olmo, in which the intracellular localization of the Uba2 was not explicitly tested (del Olmo et al. 1997; Lois et al. 2005). Consequently, the residual nuclear amount of E1 enzyme may explain the consistent findings that yeast strains with predominantly cytoplasmic Uba2 were viable and had no significant changes in the Smt3-modification pattern.
To study the effect of E1 solely present in the cytoplasm, I already began cloning of an Uba2 variant with a cytoplasmic membrane anchor. Such a variant would exclude the localization of any residual E1 in the nucleus and would therefore allow the phenotypic analysis of exclusively cytoplasmically localized E1.
If it proves true that the intracellular localization of SUMO E
significantly influence SUMOylation in the nucleus or in the cytoplasm, what does this mean for the mechanisms underlying SUMOylation in these two compartments?
In the case of exclusively nuclear localized E1 (scenario A), SUMO-charged enzyme Ubc9 would have to be exported into the cytoplasm to provide sufficient SUMOylating activity for modification of cytoplasmic targets (Fig. 37). Subsequently, the empty Ubc9 would be imported into the nucleus for another round of loading with SUMO by the nuclear localized E1. In the artificially created situation of exclusively cytoplasmic localized E1 (scenario B; tested in yeast strains), Ubc9 would have to be loaded in the cytoplasm and be imported into the nucleus for ensuring sufficent SUMO modifying activity in the nuclear compartment. After transfer of SUMO to a nuclear target, the empty Ubc9 would be exported to the cytoplasm for another round of SUMO transfer. If it proves true that both scenarios A and B do not cause drastic
changes of SUMOylation in either compartment, it could be deduced that both uncharged Ubc9 as well as SUMO-charged Ubc9 can shuttle in and out of the nucleus. This attractive model has some precedence, as ubiquitin was reported to serve as an import signal for the class III ubiquitin E2 enzyme UbcM2 (Plafker et al.
2004). Nuclear import of UbcM2 and interaction with its import receptor importin 11 were shown to depend on the charging of UbcM2 with ubiquitin.
Interestingly, the transport receptor importin 13 that has been shown to mediate
Figure 37: Working model of the nucleocytoplasmic transport of Ubc9. In the case of exclusively nuclear E1 the E2 Ubc9 is loaded with SUMO inside of the nucleus. Ubc9-SUMO is exported into the cytoplasm where it is required for SUMOylation of cytoplasmic targets.
Subsequently, empty Ubc9 is imported to be again loaded with SUMO for another round of SUMOylation.
nuclear import of Ubc9 has also been reported to mediate nuclear export of the eukaryotic initiation factor eIF1A (Mingot et al. 2001). This unusual double function would make importin 13 a potential candidate to mediate shuttling of Ubc9. However, since the presence of RanGTP has been shown to interfere with Ubc9/importin 13 complex formation, an alternative mechanism at least for the export of empty Ubc9 would be likely. Furthermore it would be interesting to analyze whether and how the according transport receptor(s) can distinguish between the empty and SUMO-charged form of Ubc9.
7. Perspectives
Generally, the SUMO E1 enzyme Aos1/Uba2 is unequally distributed between the nuclear and the cytoplasmic compartment. The presented work provides a detailed picture of the generation of the major nuclear pool. However, intensive studies will be needed to clarify the potential roles of active nuclear export, inhibition of nuclear import or cytoplasmic retention in the generation of the cytoplasmic pool of Aos1/Uba2.
Interestingly, preliminary results indicate that the intracellular localization of Aos1/Uba2 might not be of key importance for SUMOylation, raising the possibility that Ubc9 may play a critical role providing activated SUMO in different cellular compartments. If this proves true, it will be very interesting to further investigate the mechanisms underlying the intracellular localization of the E2 Ubc9. Here, it would be particularly interesting to study the mechanisms underlying SUMOylation of targets in the plasma membrane of synapses. The long distance from the nucleus, where most E1 and E2 is located, points towards an additional yet unknown mechanism that assures the local presence of sufficient SUMOylating activity. There, detailed analysis will be needed to elucidate whether cell type-specific or signal-triggered differences in the intracellular localization of the SUMO E1 and E2 enyzems exist.
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