HyperISGylation of Old World Monkey ISG15 in Human Cells

Pattyn, Els; Verhee, Annick; Uyttendaele, Isabel; Piessevaux, Julie; Timmerman, Evy; Gevaert, Kris; Vandekerckhove, Joël; Peelman, Frank; Tavernier, Jan

This variability in ISG15 sequence may indicate a redundant function of ISG15. Alternatively, it could point towards a role for ISG15 in the immune system, since high interspecies sequence divergence is very often associated with genes involved in host defense. Organism-specific niche occupation may lead to distinct repertories of invading pathogens causing species-specific pressures for adaptation of the host immune system [41, 42] . This increased evolutionary rate in immune genes may be further enhanced by the high mutation rates of the pathogens [43] . In line with the assignment of a specific role for ISG15 in host defense, naturally occurring loss-of-function ISG15 mutants have not yet been observed sofar, whereas a duplication of the ISG15 gene has been seen in crucian carp [44] . Although the precise function of ISG15 remains enigmatic, several lines of evidence point to its role as an antiviral agent. ISG15 is one of the most prominently induced genes upon type I IFN treatment, and several viruses such as Influenza B and SARS have developed mechanisms to counteract ISG15 function [9, 20] . ISG15 was also found to be critical for the IFNmediated inhibition of HIV replication and release [25] . Moreover, although ISG15 knock-out mice were initially found to be as vulnerable to viral infections as their wild type countermates [45] , a subsequent study discovered ISG15 knock-out mice to be more vulnerable to Influenza, Herpes and Sindbis viral infection [24] .