Except where indicated, all DNA manipulation was done following standard methods. Plasmids were cloned and grown in Escherichia coli DH5a or SURE2 (Stratagene). Routinely plasmid DNA was purified on CsCl gradients. The plasmids pJAT-lacZ, pGAS-luc, and pIFNb-luc were the kind gifts of Prof Steve Goodbourn, St. George's Hospital Medical School, London, United Kingdom. The pGL3-Mx1P-luc was kindly provided by Prof Georg Kochs, Department of Virology, University of Freiburg, Germany. The following plasmids were used for the ISG15ylation and ubiquitination experiments: pCAGGS.MCS-6HismISG15, and plasmids expressing mHerc6, Ubcm8 and mUbE1L were provided by Prof Deborah J. Lenschow, Washington University School of Medicine, St. Louis, Missouri. Plasmid pHA-CCHFV-L1-354 is in pCAGGS-MCSII and was the gift of Dr Natalia Frias-Staheli, Mount Sinai School of Medicine, New York.