Sumoylation at the Host-Pathogen Interface

Wilson, Van G.

While there are only a limited number of viral proteins known to target either SAE or SUMO ligases, pathogen proteins affecting Ubc9 are more numerous, suggesting that Ubc9 is a very effective cellular target for manipulating sumoylation either globally or for specific substrates. Note that most sumoylated proteins, including pathogen proteins, interact with Ubc9 as part of the sumoylation process, however, the focus in this section will only be on interactions that alter or potentially alter Ubc9 function. Examples have now been documented for both global sumoylation increases and decreases mediated by different pathogens, so both scenarios apparently can provide benefit in a pathogen-specific manner. The two examples of pathogen-dependent decreases in sumoylation via effects on Ubc9 are the Listeria monocytogenes LLO protein [88] and the HPV E6 protein [89] . L. monocytogenes is a facultative intracellular human pathogen associated with foodborne illnesses. Infection of HeLa cells with L. monocytogenes results in a general decrease in overall SUMO1 and SUMO2/3 conjugates. This decrease does not require bacterial entry into the cells, but is dependent on a known virulence factor, the listeriolysin O (LLO). Administration of purified LLO to cells also decreased sumoylation, but had no effect on in vitro sumoylation indicating that LLO was not directly inhibiting enzyme activity. Cell culture studies revealed that LLO was reducing intracellular Ubc9 levels with no effect on SAE, and a similar LLO-dependent decrease in Ubc9 was observed in an infected mouse model. Over expression of SUMO1 or SUMO2 in infected HeLa cells led to increased overall sumoylation and significantly decreased numbers of intracellular bacteria at seven hours postinfection, indicating that sumoylation is detrimental to bacterial reproduction and must be reduced to allow optimal pathogen growth. Mechanistically, the reduction of Ubc9 was not at the transcriptional level and could not be prevented by proteasome inhibition. However, an aspartyl protease inhibitor partially restored Ubc9 levels in the presence of LLO, suggesting that LLO may be acting through a cellular protease that can target Ubc9. Related toxins from Clostridium perfringens and Streptococcus pneumonia also reduced Ubc9 levels, indicating that host sumoylation may be generally restrictive to other bacterial pathogens and that these pathogens have evolved mechanisms to counteract this host system.