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

ISG15 is upregulated upon viral infection. Its role in antiviral defense is underscored by viral mechanisms to counteract ISG15 function. For example, the influenza B Non-Structural NS1B protein binds ISG15, thereby preventing its association to UbE1L [9] . Also the papain-like protease of the Severe Acute Respiratory Syndrome (SARS) Coronavirus, counteracts ISG15 functioning by removing it from its substrate [20] . The Hepatitis C virus NS3/4A protease cleaves IFN Promoter-Stimulator-1 (IPS-1) leading to reduced ISG15 expression and conjugation [21] . In a more direct way, ectopic expression of ISG15 in cells lacking a functional IFN response reduces Newcastle Disease Virus and Influenza Virus replication [22] , and also overcomes fatal intracerebral infection in IFNaR 2/2 mice by Sindbis Virus [23] . ISG15 knock-out mice proved to be more sensitive to Influenza, Herpes and Sindbis viral infection [24] . An inverse dose-response correlation of exogenously expressed ISG15 and release of Human Immunodeficiency Virus (HIV) virions is also found and suppression of ISG15 expression by siRNA counteracts IFN-mediated inhibition of HIV virion release [25] .