The antiviral activities of ISG15

Abstract

Post-translational protein modification is an important strategy for the regulation of the cell proteome independent of the need for new gene expression. Ubiquitin and ubiquitin-like modifiers mediate the regulation of protein levels, signaling pathways, vesicular trafficking, and many other cellular processes through their covalent conjugation to proteins. Interferon stimulated gene 15 (ISG15) is a ubiquitin-like modifier induced by type I interferon. In addition to conjugating to potentially hundreds of target proteins, ISG15 can be found in an unconjugated form both inside of the cell and released from interferon stimulated cells into the extracellular environment. Due to its robust expression after type I interferon stimulation and the broad panel of proteins that it targets, ISG15 has drawn much attention as a potential regulator of the immune response and has been shown to mediate protection in a number of different viral infection models. Here we will review the current state of the field of ISG15, the viruses against which ISG15 mediates protection, and the mechanisms by which ISG15 exerts antiviral activity.

Keywords: ASLV; CHIKV; Chikungunya virus; ESCRT; HIV-1; HPV; HSV-1; IRF3; ISG15; JNK; Jun N-terminal kinase; LCMV; MEF; NDV; NK; Newcastle disease virus; PKR; RIG-I; SeV; Sendai virus; VLP; VSV; WNV; WT; West Nile virus; avian sarcoma leukosis virus; endosomal sorting complexes required for transport; herpes simplex virus 1; human immunodeficiency virus 1; human papilloma virus; innate immunity; interferon regulatory factor 3; interferon stimulated gene 15; interferons; lymphocytic choriomeningitis virus; mouse embryonic fibroblast; natural killer; protein kinase R; retinoic acid inducible gene 1; short interfering RNA; siRNA; ubiquitin-like protein; vesicular stomatitis virus; virus-like particle; viruses; wild type.

Graphical abstract

Fig. 1

A comparison between the ubiquitin and ISG15 conjugation pathways. Both ubiquitin and ISG15 are conjugated to target proteins by utilizing enzymatic cascades composed of E1, E2, and E3 enzymes. (a) In the case of ubiquitin, it achieves specificity in target protein modification through the use of multiple E2 and E3 enzymes, which can orchestrate a broad range of specific ubiquitin modifications. Ubiquitin can also conjugate to itself on multiple lysine residues to form polyubiquitin chains on target proteins that result in different downstream functional consequences for the targeted protein. (b) The ISG15 conjugation cascade is an IFN-induced cascade in which the vast majority of ISG15 conjugation utilizes UbE1L, UbcH8, and HERC5. Interaction between HERC5 and polysomes leads to the preferential ISGylation of newly translated proteins. Unlike ubiquitin, there is no evidence that ISG15 forms poly-ISG15 chains or targets proteins for degradation.