Sumoylation at the Host-Pathogen Interface

Wilson, Van G.

STUbLs (SUMO Targeted Ubiquitin Ligases) are a group of ubiquitin ligases that contain SIM motifs that target the ligases to sumoylated proteins [78] . A recent report by Boutell et al. demonstrated that the herpes simples ICP0 protein has properties suggestive of a STUbL [67] . ICP0 has 7 predicted SIM-like sequences (SLSs), and at least some of them are functional for SUMO binding. In yeast two-hybrid assays ICP0 interacts in a SLS-4 dependent manner with SUMO2/3 but not SUMO1. In contrast, in in vitro pull-down assays the C-terminal portion of ICP0 binds SUMO1 and not SUMO2/3; SLS-5 appeared to be important for this SUMO1 interaction, but other sequences may also contribute. The discrepancy between the two-hybrid and pull-down assay results was not resolved, but together they support the interpretation that ICP0 may make interactions with all the SUMO isoform. In addition to SUMO binding, ICP0 can specifically ubiquitinate poly-SUMO chains in vitro. This activity requires both the RING domain and an intact SLS-4 sequence. ICP0 SLS-4 mutants retain full ubiquitinating activity on other substrates, so the SIM motif appears necessary only for directing ICP0 to sumoylated substrates. Consistent with the in vitro results, expression of ICP0 in a stable cell line resulted in a decrease in global SUMO conjugates, including sumoylated forms of PML, and this activity was reduced though not entirely eliminated in an SLS-4 mutant. These results suggest that ICP0 is ubiquitinating sumoylated proteins and targeting them for proteasomal degradation. Thus, it appears that the SLSs of ICP0 can redirect the intrinsic ubiquitin ligase activity to sumoylated proteins, such as PML, which may contribute to ICP0's ability to overcome intrinsic cellular resistance to HSV. Given the growing number of known viral ubiquitin ligases [79] , it would be surprising if others were not also STUbLs.