Sumoylation at the Host-Pathogen Interface

Wilson, Van G.

One of the important host cell proteins whose sumoylation is specifically impacted by pathogen proteins is the cell cycle regulator, pRB [97] . pRB is a tumor suppressor that inhibits cell cycle progression by blocking E2F activity until phosphorylation of pRB by cyclin kinases at late G1/early S phase releases E2F [98] . Ledl et al. showed that pRB is sumoylated at lysine 720 in the B-box motif of the so called pocket region, and that the hypophosphorylated form of pRB is preferentially sumoylated [97] . Lysine 720 is part of a "lysine cluster" that contributes to interaction with LxCxE containing proteins such as the adenovirus E1A protein and the papillomavirus E7 protein. Both E1A and E7 bind pRB and displace E2F to stimulate cellular entry into S phase which is critical for viral replication. As suspected from the known binding surfaces, addition of E1A protein to an in vitro sumoylation reaction prevents pRB sumoylation, and this inhibition requires direct E1A-pRB interaction. Similarly, in vivo expression of either E1A or E7 inhibits pRB sumoylation. Lastly, they showed that sumoylation of pRB decreases its repressive activity on an E2F driven promoter, indicating that sumoylation is an actual regulator of pRB and that E1A or E7 inhibition of sumoylation would have a functional effect. Whether or not this effect on pRB function is an irrelevant consequence of E1A or E7 protein binding or actually contributes to creation of the permissive environment has not been investigated.