Sumoylation at the Host-Pathogen Interface

Wilson, Van G.

Elegant studies from Roger Everett's group found that PML and other NB proteins, such as Sp100 and Daxx, have SIM motifs that are required for recruitment of these proteins to herpes simplex virus (HSV) replication foci [65] . Absence of the SIM motif does not affect PML mobility or normal assembly into NBs, so the SIM motif seems to function primarily to direct the formation of NB protein complexes on viral replication complexes. These NB complexes are transient in wild type HSV infection due to their disruption by the early gene product ICP0. However, an HSV ICP0 null mutant is normally highly defective for replication unless PML is depleted, suggesting that recruitment of the NB proteins creates a repressive environment at the replication foci that would block viral replication unless overcome by ICP0 [65, 66] . Reintroduction of wild type PML decreases viral production by the ICP0 mutant while reintroduction of a SIM minus PML does not, strongly implicating the SIM motif in targeting PML to the replication foci [65] . Consistent with the importance of the PML SIM, viral replication foci were found to have a significant deposition of SUMO1 and SUMO2/3 which could serve as the platform for SIM binding. Furthermore, knockdown of the sole SUMO conjugating enzyme, Ubc9, reduces accumulation of SUMO1 and SUMO2/3 signals at the viral foci suggesting that de novo sumoylation is needed for the accretion of the sumoylated proteins at these sites [67] . Ubc9 knockdown also results in greatly enhanced replication of the ICP0 null mutant which is again consistent with sumoylation contributing to intrinsic anti-viral activity. Based on these observations the authors proposed that sumoylated proteins assemble on the viral genomes and serve as the signal to recruit PML and other SIM containing NB proteins to viral replication complexes. Assembly of PML, Sp100, and Daxx would normally inhibit HSV replication if not counteracted by the ICP0 protein (see below). Presumably this SIM-SUMO dependent recruitment could be a general mechanism that accounts for PML anti-viral activity on various other invading viral genomes. What the actual sumoylated proteins are and how they might be directed to the nascent viral replication foci is unknown, but could be related to the viral genomes eliciting the cellular DNA damage response.