The interferon-induced ubiquitin-like modifier ISG15 can be conjugated to proteins (ISGylation) to modify their function. ISGylation is markedly induced following viral infection as part of the immune response, but the viral substrates and strategies that are used to counteract the antiviral response are not well defined. Kim et al. show that ISG15 expression and protein ISGylation are induced following infection with human cytomegalovirus (HCMV). Increased ISGylation inhibited viral growth as well as virion release at low multiplicity of infection. The levels of ISG15 and ISG15 conjugates decreased later during the course of infection, which was dependent on the viral protein IE1. Furthermore, the viral protein pUL26 interacted with ISG15 and was ISGylated, which decreased its stability and inhibited its ability to downregulate nuclear factor-κB (NF-κB) signalling. Interestingly, pUL26 had an inhibitory effect on ISGylation during the late phase of infection and thus, in addition to IE1, also combats the ISG15-mediated antiviral response.
Kim, Y. J. et al. Consecutive inhibition of ISG15 expression and ISGylation by cytomegalovirus regulators. PLoS Pathog. http://dx.doi.org/10.1371/journal.ppat.1005850 (2016)