Interferon-stimulated gene 15 and the protein ISGylation system

Abstract

Interferon-stimulated gene 15 (ISG15) is one of the most upregulated genes upon Type I interferon treatment or pathogen infection. Its 17 kDa protein product, ISG15, was the first ubiquitin-like modifier identified, and is similar to a ubiquitin linear dimer. As ISG15 modifies proteins in a similar manner to ubiquitylation, protein conjugation by ISG15 is termed ISGylation. Some of the primary enzymes that promote ISGylation are also involved in ubiquitin conjugation. The process to remove ISG15 from its conjugated proteins, termed de-ISGylation, is performed by a cellular ISG15-specific protease, ubiquitin-specific proteases with molecular mass 43 kDa (UBP43)/ubiquitin-specific proteases 18. Relative to ubiquitin, the biological function of ISG15 is still poorly understood, but ISG15 appears to play important roles in various biological and cellular functions. Therefore, there is growing interest in ISG15, as the study of free ISG15 and functional consequences of ISGylation/de-ISGylation may identify useful therapeutic targets. This review highlights recent discoveries and remaining questions important to understanding the biological functions of ISG15.

FIG. 1.

A domain diagram of ubiquitin and ISG15. ISG15, interferon-stimulated gene 15; LRLRGG, Leu Arg Leu Arg Gly Gly.

FIG. 2.

Protein ISGylation and de-ISGylaiton system. UbE1L catalyzes adenylation and then forms a thioester bond with the C-terminal end of ISG15. Activated ISG15 is transferred to the ISG15-conjugating enzyme, UbCH8. ISG15 and UbCH8 are also covalently linked via a thioester bond. With the help of ISG15 E3 ligase, the C-terminus of ISG15 is conjugated to the ɛ-amine group of lysine on the substrate. Ubiquitin-specific proteases 18 removes ISG15 from the substrate.