Sumoylation at the Host-Pathogen Interface

Wilson, Van G.

The high risk HPV E6 proteins, 16E6 and 18E6, also reduce both intracellular Ubc9 levels and overall sumoylation; low risk 11E6 had no effect on Ubc9 or sumoylation, but other low risk E6 proteins were not tested so the generality of this observation is not known [89] . High risk E6 proteins are known to induce proteasomal degradation of several host proteins via direct binding of the target and recruitment of a host ubiquitin ligase called E6AP [90] . Consistent with a possible proteasomal degradation mechanism, both 16E6 and 18E6 bound Ubc9 in pull-down assays. Additionally, the in vivo reduction in Ubc9 levels was E6AP dependent, and there was no effect at the transcript level. However, standard proteasomal inhibitors were relatively ineffective in restoring Ubc9 levels so the mechanism of degradation remains uncertain. Furthermore, the critical sumoylated substrates have not been identified and the direct advantage to the virus of reduced sumoylation has not been established, so the biological contribution of this E6 activity is uncertain. Nonetheless, the fact that E6 targets two sumoylation enzymes, Ubc9 and PIASy (discussed above), suggests that modulation of sumoylation is important to the viral life cycle. Interestingly, another HPV protein, the minor capsid protein L2, increases global host sumoylation, though the mechanistic basis for this increase has not been explored and may not involve Ubc9 [91] . Since L2 is a late protein and E6 an early protein, it is possible that both up and down regulation of sumoylation are required at different stages of the viral cycle.