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We believe that G protein coupled receptors K1813 is the major sumoylation site in FLASH based on two observations. First of all, without overexpression of SUMO-1 or SUMO E3 ligases the main modified band detected corresponds to a K1813-conjugated protein (Fig. 2B). Secondly, there are other possible sumoylation sites in the FLASH full-length protein sequence, but Ubc9 interacts only with the region of FLASH surrounding the LK1813SE motif and most likely not with other parts of FLASH (Fig. 1).
Although the activity of FLASH was repressed when abrogating sumoylation of K1813 by point mutation, co-transfection of FLASH with the SUMO-specific protease SENP1 increased FLASH activity in a Gal4-tethering assay (Fig. 4A). The K1813R mutant was activated by SENP1 as well (Fig. 4C). So how does SENP1 activate FLASH if not through desumoylation at K1813? Several explanations are possible, related to other sumoylation sites, localization or indirect effects.
There are several possible sumoylation sites throughout the FLASH protein sequence that might be conjugated despite weak affinity for Ubc9. The presence of non-consensus SUMO-conjugation sites is another possibility. Such sites may have repressive effects. A more thorough analysis of sumoylation of FLASH will be needed to identify these or exclude ingestive feeders possibility.