Sumoylation at the Host-Pathogen Interface

Wilson, Van G.

Downstream of the TLRs, sumoylation of both murine IRF3 and IRF7 in response to viral infection has been reported [50] . Interestingly, sumoylation defective mutants of either protein led to increased interferon gene expression after viral infection suggesting that sumoylation is a negative regulator at this stage of the pathway. However, a subsequent study examining endogenous human IRF3 came to the opposite conclusion [51] . Ran et al. showed that sumoylation of human IRF3 competed with ubiquitination and protected IRF3 from degradation. When sumoylation of IRF3 was elevated by reduction in the levels of the SENP2 SUMO protease it resulted in decreased viral replication, suggesting that sumoylation was a positive regulator of innate immunity. Whether these conflicting results reflect differences in human versus murine IRF3 or differences in the experimental approaches, it is clear that sumoylation is a contributor to the regulatory process that governs the initiation of the interferon response. Consequently, it is likely that viruses have evolved mechanisms to thwart or usurp this upstream portion of the pathway as well as the documented viral effects on downstream effectors such as PKR and 2',5'-oligoA synthetase [52] . While there are not yet examples of viruses specifically targeting the sumoylation of TLRs or their signaling pathways, several viruses can alter global cellular sumoylation (see sections below) which could impact the functionality of the innate immune response.