Eukaryotic translation initiation factor 4F (eIF4F) is a protein complex that mediates recruitment of ribosomes to mRNA (Gingras et al. 1999). eIF4F contains complex of cap-binding protein eIF4E, scaffold protein eIF4G, and RNA helicase eIF4A. There are three eIF4E-family members in mammals termed eIF4E-1 (eIF4E), eIF4E2 (4EHP), and eIF4E3, of which both eIF4E and eIF4E3 are able to bind to eIF4G to facilitate translation initiation. However, 4EHP does not interact with eIF4G and thus cannot function in ribosome recruitment. 4EHP competes with eIF4E or eIF4E3 for binding to the RNA 5? cap structure and prevents translation initiation. ISGylated 4EHP has a much higher cap structure binding activity, suggesting a regulatory function of ISGylation in protein translation during immune responses (Okumura et al. 2007, Joshi et al. 2004).