Emerging role of ISG15 in antiviral immunity

Abstract

Cells express a plethora of interferon-stimulated genes (ISGs) in response to viral infection. Among these is ISG15, a ubiquitin-like protein (UBL) that can be covalently attached to both host and viral proteins. Here we review recent advances toward understanding the role and mechanism of ISG15 modification in antiviral defense.

Figure 1. ISGylation and Its Antiviral Mechanisms

A. ISG15, like ubiquitin, is attached to substrates in a three-step enzymatic cascade. In the first step, ISG15 is “activated” by UBE1L in an ATP-dependent process. ISG15 is then transferred to the E2 UBCH8, and subsequently to a target protein through the E3 HERC5. Like ubiquitin, ISG15 is conjugated to a lysine on the target protein through a C-terminal glycine-glycine motif. B. Type I interferons (IFNs) induce expression of ISG15 and ISGylation machinery including HERC5. During infection with influenza A, nonstructural protein 1 (NS1A) protein is ISGylated on lysine 41. ISGylation inhibits the binding of NS1A to the nuclear import factor importin-α. Mutation of this lysine largely protects influenza A from the antiviral actions of type I IFN. C. HERC5, likely due to its association with ribosomes, broadly targets newly-synthesized proteins for ISGylation. ISGylation of certain viral proteins, including those that make up the capsid, could have a dominant negative effect by interfering with the precise assembly of higher order structures. Thus ISG15 can cause a significant impairment in viral infectivity despite ISGylation of only a small percentage of the target proteins.